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Brain Research Reviews 32 Ž2000. 16–28
Short review
Electrical synapses, a personal perspective žor history/
Michael V.L. Bennett
Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park AÕenue, Bronx, NY 10461, USA
Gap junctions are the morphological substrate of one class of electrical synapse. This memoir records the author’s involvement in the
development of our knowledge of the physiology and ultrastructure of electrical synapses. The answer to whether neurotransmission is
electrical or chemical is either. One lesson is that Occam’s razor sometimes cut too deep; the nervous system does its operations in a
number of different ways and a unitarian approach can lead one astray wM.V.L. Bennett, Nicked by Occam’s razor: unitarianism in the
investigation of synaptic transmission, Biol. Bull. 168 Ž1985. 159–167x. Electrical synapses can do many things that chemical synapses
can do, and do them just as slowly. The new molecular, cellular and physiological techniques will clarify where gap junctions and
electrical coupling do and do not occur and permit experimental manipulation with high specificity. q 2000 Elsevier Science B.V. All
rights reserved.
Keywords: Gap junction; Electrical synapse; Connexin; Coupling
1. Introduction .
2. An aside on ‘‘ephapses’’ and other nomenclatural niceties .
6. Electrical versus chemical
7. An aside about evolution .
3. The first connexin based electrical synapses!
4. What next? Electric organ control systems
5. Fast motor systems .
8. Romance in academia
Acknowledgements .
1. Introduction
It seems like yesterday that I started to work on electrical communication between neurons. Well, actually not, it
seems quite a long time ago, and the field, and I, have
matured significantly over the years. The operation of
neurons at the level of electrical signaling, at least at the
level of questions that most of us were asking more than
Tel.: q1-718-430-2536; fax: q1-718-430-8944; e-mail: [email protected]
0165-0173r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 1 6 5 - 0 1 7 3 Ž 9 9 . 0 0 0 6 5 - X
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
40 years ago, is pretty well understood, not completely of
course, but there are no very large black boxes. It seems
much more like yesterday, and is, that I last wrote a review
on the development of knowledge of electrical transmission w73x. What has happened in the last couple of years?
Aside from substantial but incremental progress, there has
been the discovery of neuron specific connexins w26,63x
and of connexin diseases that involve the nervous system
w15,22,38x. Although no diseases of electrical synapses
have been discovered yet, there are sure to be mutations of
neuron specific connexins, whether or not the mutations
lead to an observable phenotype. Interestingly, mutations
of Cx26 and Cx32, which are expressed by some neurons
in the CNS, have yet to show any phenotypic changes in
those neurons. Gene targeting is progressing through the
connexin gene family. And there is the discovery that gap
junctions of the Ecdysozoa Žthe nematode, arthropod line.
are encoded by a gene family completely unrelated to the
connexins, although there are many convergent Ž not conserved. properties between the junctions encoded by that
gene family and by the connexins. Since the new connexins and connexin diseases are extensively discussed in this
volume by others more directly involved in the research,
and I just participated in writing a review of connexin
diseases w15x, I will make this presentation more an oral
history than an integrative summary and analysis.
One does not have to have been at Oxford to define a
synapse as a specialized site of functional interaction
between neurons, although Sherrington and Eccles Žand I.
were. By this definition gap junctions form one class of
electrical synapse w13x. Another kind of electrical synapse
mediates short latency inhibition of the Mauthner cell of
teleost fishes and possibly mammalian cerebellar Purkinje
cells; this form of electrical transmission is not mediated
by gap junctions, and involves different junctional specializations Žsee below. w28x. In addition, there probably are
electrical interactions that occur between closely apposed
cells without obvious gap junctions or specializations other
than the absence of interposed glia w28,36,67x. Whether
these sites are to be considered synapses, i.e., specialized,
or ephapses, i.e., incidental or accidental sites of interaction, may become clear with greater knowledge of the
developmental mechanisms. Without deciding on a name
one can still describe the electrical interaction, which does
indeed appear to be uniquely associated with the close
2. An aside on ‘‘ephapses’’ and other nomenclatural
Angelique Arvanitaki w1x coined the term ephapse from
the Greek to mean an apposition that is not quite so close
as a synapse Žaccording to my Greek–American colleague,
George Dimitrios Pappas.. She used it to denote what she
thought of as artificial synapses, which she made by laying
one axon along side another where the ‘‘action currents’’
generated during an impulse in one axon altered the excitability of the other axon. This terminology suggests that
she thought synaptic transmission was electrical, at least
that is my recollection, and, in the spirit of oral history, I
will not go to the library to try to confirm that view.
Ephapse then came to be used for incidental contacts in the
nervous system, particularly where activity in one or more
axons excited other axons. These days one might wonder if
actual gap junction electrical synapses were formed between axons in injured tissue.
My mentor at that time, Harry Grundfest, had embraced
the idea that chemical transmission was mediated at electrically inexcitable membrane, i.e., in explicit, modern
terms that the conductance of the neurotransmitter receptors was independent of membrane potential and only a
function of transmitter concentration. To keep transmission
at synapses chemically pure, he decided to use ephapse to
denote morphological specializations between neurons
where transmission was electrical. Although my Oxford
education led me to disagree with this practice, to keep
peace in the laboratory I used ‘‘electrotonic junctions’’ for
one type of what I now freely term electrical synapses. At
that time I felt that ephapse connoted artificiality or incidentality, which downgraded the importance of my work.
Electron microscopy now makes it clear that gap junctions
are closer appositions than occur at chemical synapses,
and, if one were starting over, one would call chemical
synapses ephapses and gap junctions between neurons
synapses. In my view both he and Jack Žlater Sir John.
Eccles made a mistake in thinking that only one mode of
transmission could be synaptic, but Eccles was better at
changing his mind w14x.
I recall when David Potter presented his and Edward
Furshpan’s work w31x on the crayfish giant motor synapse
at the Monday night electrobiology seminars at the Marine
Biological Laboratory ŽMBL, Woods Hole.. This work and
the independent studies of Akira Watanabe w70x on the
cardiac ganglion of the mantid shrimp were the first
unequivocal demonstrations of electrical transmission between neurons. The electrobiology sessions were organized
by Harry, who welcomed airing of all views, and were
known as the Monday Night Fights because of the sometimes heated discussion and by analogy with the Friday
Night Fights, a popular program at the time showing
professional boxing matches. Harry suggested in the discussion period, or possibly before, since interruptions were
not uncommon, that they should call their rectifying
synapse an ephapse, because it was electrical although it
was electrically inexcitable. David pointed out to him with
evident pleasure that the junctional conductance was a
function of voltage and thus was electrically excitable.
Harry did not have a good retort, which was unusual for
him. Of course gap junctions between segments of the
septate axon are electrically linear over a wide range
w37,71x, while connexin based gap junctions all show some
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
degree of dependence on transjunctional voltage Že.g., Ref.
In a collection of gap junction papers, it should not be
necessary to obsess about the relative merits of chemical
and electrical synapses. We workers in the field for the
most part think highly of what we do. Still, in this contribution it may be worthwhile to do a little complaining,
qvetching or whining, depending on one’s ethnic origin.
For example, consider the ‘‘medical subject headings’’
ŽMeSH. for the PubMed data base. Under ‘‘Synapses’’ is:
Specialized junctions at which a neuron communicates
with a target cell. At classical synapses, a neuron’s
presynaptic terminal releases a chemical transmitter
stored in synaptic vesicles which diffuses across a
narrow synaptic cleft and activates receptors on the
postsynaptic membrane of the target cell. The target
may be a dendrite, cell body, or axon of another neuron,
or a specialized region of a muscle or secretory cell.
Neurons may also communicate through direct electrical connections which are sometimes called electrical
synapses; these are not included here but rather in GAP
And then under ‘‘Synaptic Transmission’’:
The communication from a neuron to a target Žneuron,
muscle, or secretory cell. across a synapse. In chemical
synaptic transmission, the presynaptic neuron releases a
neurotransmitter that diffuses across the synaptic cleft
and binds to specific synaptic receptors. These activated
receptors modulate ion channels andror second-messenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions.
Thus, to look for the latest in electrical transmission or
electrical synapses, one has to take a somewhat devious
route and examine all those other citations that come along
with gap junctions and nervous system. Looking for earlier papers is more complicated because Gap Junctions as a
MeSH term was not introduced until 1994, and you cannot
search for the phrase ‘‘electrical synapse’’, although ‘‘electrically synaptic transmission’’ is in the Compound Word
Dictionary and yields 12 citations. Another bit of whining
for the in-group: even some workers in the gap junction
field have trouble using electrical with respect to PSPs, no
doubt influenced by Harry. Korn and Faber write about
‘‘coupling potentials’’ at electrical synapses rather than
PSPs. J.G.R. Jefferys w36x in a Physiological Review considers ‘‘four classes of non-synaptic interaction, mainly in
the mammalian brain’’ of which the first is ‘‘Electrotonic
Žand chemical. coupling through gap junctions’’. Yet he
also writes of ‘‘gap junctions, which commonly serve as
electrical synapses in invertebrates but appear to be used
less often for electrical signaling in vertebrates’’.
The reader may feel that there is too much discussion of
terminology here. There probably was too much quarrelling over nomenclature, but some of the controversy
represented real differences in concepts rather than egodriven preference. We should all be familiar with Feldberg’s Dictum, which is that a scientist would rather use
another scientist’s toothbrush than his terminology. I believe I heard this from ŽSir. Bernard Katz, who cited it in
one of his lectures. It is a delightfully apt phrase in that
words have a flavor of their origin andror meaning. When
I was a child, a not uncommon punishment for use of foul
language was washing the offender’s mouth out with soap;
thus, the mystical view seems to be that dirty words
physically soil the speaking apparatus. In my own case,
speaking of alpha and beta connexins make me want to
brush my teeth with my toothbrush.
Jean Paul Changeaux once chided me for calling gap
junctions between neurons electrical synapses, when the
same structures were called gap junctions when they occurred between non-neuronal cells. The venue was a sidewalk cafe in Paris, and the statement should not be taken
very seriously. Moreover, as chemical interactions between
non-neuronal cells have become more widely described
and as the molecules responsible for exocytosis and endocytosis at synapses have proved to have homologs in
non-neuronal cells, the same criticism might be lodged
about the terminology for chemical synapses.
3. The first connexin based electrical synapses!
The supramedullary neurons of the puffer fish,
Spheroides maculatus, were the subject of my first experiments at the MBL in Woods Hole. These large neurons
Ž0.2–0.3 mm in diameter. sit on the dorsal surface of the
medulla and can be seen with the naked eye, at least with
my eyes at that time ŽFig. 1.. I no longer remember where
Harry Grundfest found out about them, possibly from
Shigehiro Nakajima and Susumu Hagiwara, who later
studied their action potential generation, but the cells were
known to early comparative anatomists including Sigmund
Freud. Large neurons were of interest, because they were
relatively easy to study with sharp intracellular microelectrodes and patch electrodes were far in the future. The
function of the neurons was unknown, and we were able to
show that they were effector cells sending their axons out
the dorsal roots to the skin. But nothing obvious happened
in the skin when they were stimulated. Recent data demonstrate that they contain gastrinrcholecystokinin and innervate mucous glands w29x, and a secretomotor function
should be more carefully investigated. But that is comparative physiology, which is primarily of interest to NSF.
What is more relevant to general physiology and this
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
Fig. 1. Anterior spinal cord of the puffer viewed from the dorsal side. The posterior limit of the cerebellum is to the left. The supramedullary neurons are
the large round cells, about 250 mm in diameter, that are located on the surface of the cord. Several of the cells that had been penetrated for intracellular
recording are dark because of increased staining by toluidine blue applied to the surface wfrom Ref. w19xx.
discussion is the observation that they fire synchronously
in response to cutaneous inputs.
The initial observation of synchronous firing was the
accidental result of putting two electrodes in adjacent cells
when trying to get two into one cell for separate current
application and voltage recording. What was one to think
in 1957 when one saw synchronous firing? I thought that a
higher level synchronizing center was exciting the
supramedullary neurons, and that the large depolarization
that initiated the overshooting spike was a PSP Žimplicitly
chemically mediated. generated by inputs from that center.
One afternoon Eccles was visiting the laboratory while I
was recording. He looked at the oscilloscope screen, saw
the two component spike and said of my synchronizing
input ‘‘That’s an initial segment spike’’. He advised me to
advance an electrode beneath the cluster of cell bodies to
record from the axons directly. I tried it, and, of course, he
was right. It was quite easy to find two component spikes
that characterized an axonal recording and then to hyperpolarize one by one the overlying somata until the soma of
origin was identified. But in addition to finding axon
spikes and clarifying the nature of the two components of
the spike recorded in the soma, I also found coupling. The
cells are coupled by gap junctions between their axons
w20x. Thus, when one hyperpolarized an overlying cell
body that did not belong to an axon being recorded from,
the hyperpolarization due to coupling was larger than in
the cell body giving rise to that axon and occasionally big
enough that even the unprepared mind could not miss it.
We were rapidly convinced that the coupling was responsible for the synchronization. What had not been obvious is
that mutual excitation between the cells was electrical. An
action potential directly evoked in one cell could spread to
the rest of the cells in the cluster and this spread showed
paired pulse facilitation, although we did not call it that.
The period of increased excitability could be as long as
200 ms, which we thought suggested a chemical rather
than electrical mechanism, but subsequently it proved to be
explained by a long-lasting depolarizing afterpotential. And
the rest is history.
Let us be frank here. The presence of coupling was put
in a footnote in the 1959 puffer papers and discussed at
slightly greater length in a few abstracts. Full publication
took about 7 years w9,20x. NIH was more forgiving and the
race for priority was not so hectic as it is now. Nor did we
know that connexins and Ecdysozoan gap junction proteins
were different families.
Although many of the implications of electrical coupling of supramedullary neurons were not immediately
obvious and only became clear as other examples of
coupling were discovered, the system has relevance to
mammalian systems. First, electrical synapses can serve a
synchronizing function, but the degree of synchronization
need not be very precise; the spikes in different cells in the
cluster can be quite dispersed in time. Propagation of
impulses between cells can be slow compared to the delays
at chemical synapses and in some species the safety factor
for propagation can be less than one in that an impulse in
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
one cell is not always accompanied by an impulse in all
the other cells; the safety factor depends on the presynaptic
action potential, strength of coupling and excitability of the
postsynaptic cell. These conclusions could also have been
drawn from Watanabe’s mantid shrimp data w70x. He observed coupling of bursting neurons controlling heart rate.
He thought the cells were connected by cytoplasmic
bridges, which is probably wrong, but recognized the
synchronizing function of the coupling. Second, the synchronizing function of electrical synapses involves hyperpolarization of more positive cells, as well as depolarization of more negative cells. Coupling is a two way street,
and a significant fraction of a cell’s input conductance can
be the input conductance into its electrical synapses with
other cells. Third, impulses are more likely to spread
between cells when they are depolarized by other synaptic
inputs, chemical as well as electrical, and there can be both
spatial and temporal summation of electrical PSPs. All
these features are trivial if not obvious consequences of
coupling by gap junctions. Although we were concerned
about the morphological basis of electrical coupling, the
puffer was not a great preparation in which to look for gap
junctions, and associating gap junctions with electrical
transmission came later.
4. What next? Electric organ control systems
This was not the time when hunting for further electrical synapses crossed my mind, but it proved possible to
blunder upon them. Harry Grundfest had been interested
before I arrived at P & S Žthe College of Physicians and
Surgeons of Columbia University. in how weakly electric
fishes generated their electric pulses and how the organ
discharge was controlled. These fishes, depending on the
species, emit brief pulses with relatively long intervals
between them or pulses that are separated by an interval
comparable to the pulse duration ŽFig. 2.. The former
group, pulse fish, modulated their discharge frequency in
response almost any mode of stimulation, whereas the
latter group, wave fish, tended to have a very constant
frequency. Stimulating the spinal cord of wave fish did not
cause acceleration. When examined carefully, there was a
slight phase advance, which we now know to be due to
depolarization from antidromic activity spreading into the
pacemaker nucleus in which the frequency is set. Still, the
constancy was impressive in the face of a stimulus that
activated sensory inputs and caused a dramatic acceleration in the pulse fish. Akira Watanabe, he who had shown
the coupling between cardiac ganglion cells of the mantid
shrimp, took a more subtle approach. Asking what a wave
fish would do when presented with a stimulus of nearly its
own frequency, which would certainly happen in the gregarious species, he discovered the jamming avoidance
response. Presented with a sinusoidal stimulus near its own
frequency, the fish either accelerates or decelerates its own
Fig. 2. Patterns of electric organ discharges in teleosts. ŽA. An electric
catfish, Malapterurus electricus, activity recorded head positivity upward. Mechanical stimulation evoked a train of five pulses with a
maximum frequency of ;190rs. ŽA . A single pulse could also be
evoked. Recorded at a faster sweep speed. ŽB–D. Discharge of weakly
electric gymnotids, South American fishes, recorded head positivity
upwards. ŽB. A pulse fish, Gymnotus carapo, emits pulses at a basal
frequency of ; 35rs. Touching the side of the fish at the time indicated
by the downward step in the lower trace caused an acceleration up to
;65rs. ŽB . At a faster sweep speed, the single pulses show three
phases, initially head negative. ŽC. Sternopygus macrurus, a wave fish,
discharges at ; 55rs. The horizontal line indicates the zero potential
level. The discharge has little DC component. ŽD. Sternarchus
(Apteronotus) albifrons, a high frequency wave fish, emits biphasic
pulses at ;800rs. The horizontal line indicates the zero potential level.
Calibrations in volts and milliseconds wfrom Ref. w11xx.
discharge to increase the frequency difference and thereby
reduce interference. The central pathways and physiology
of this response and of electroreception in general were
extensively and productively explored by Walter Heilegenberg, who was tragically killed in an airplane crash w32x.
Walter had many gifted collaborators.
With the background of gross stimulation of the electric
fish and after more or less exhaustingly reporting the
modes of operation of electric organs w8,11x, Emilio Aljure
and I looked in the spinal cord and then medulla of
mormyrid electric fishes. These species are pulse fishes
and generate very brief discharges - 0.5 ms in duration.
Since the generating cells, or electrocytes, emit bi- or
triphasic pulses, very precise synchrony is required to
prevent cancellation of out of phase activity. Although the
electromotor neurons were not visualizable in the spinal
cord, it was not that hard to penetrate neighboring cells
and demonstrate electrotonic coupling directly. In these
species, the electromotor neurons showed quite large diameter dendrodendritic connections Žand with uniform staining the cells can appear syncytial or multinucleate, Fig. 3..
Now here was a preparation that one could, without shame,
ask one’s anatomical colleagues to examine. Yasuko Nakajima and George Pappas soon showed that there were close
membrane appositions between the dendrites ŽFig. 3. w17x.
We would now call these structures gap junctions, although the gap was not resolved in the early pictures. We
did suggest that ultrastructural examination could prove
useful for identifying synapses between dendrites where
electrical measurements were hard to obtain. My colleague, Dominick Purpura, at that time a mammalian
neurophysiologist, did not approve of this suggestion, but
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
Fig. 3. Neurons appearing syncytial with the light microscope, medullary electromotor relay neurons of the African electric fish, Gnathonemus sp. ŽA. In a
silver stained preparation ŽRomanes’ method. a thick process appears to connect the two cell bodies without there being any intervening membrane. ŽB.
Electron microscopy reveals membranes across these processes, between the arrows in this example. A capillary is present on the lower left. Axon
terminals Ža. form morphologically defined chemical synapses on the cell somata ŽS.. ŽC. At a similar region of apposition between spinal neurons, higher
magnification shows large regions, where the extracellular space is greatly diminished, and the membranes appear fused between the arrows.
Quasi-periodic dots in the center of the apposition in this osmicated preparation result from superposition of images of stained channels wfrom Ref. w17xx.
then he thought he was recording activity of chemical
synaptic inputs to the dendrites.
Examination of several South American Žgymnotid.
electric fishes also showed electrical coupling in the electromotor system, and we put forth the generalization that if
an organism wanted to perform a highly synchronous act,
such as an electric organ discharge, the controlling neurons
should be electrically coupled. In these electromotor sys-
tems, the precision of synchronization was greater than
could be provided by reciprocal chemically mediated excitation with its attendant synaptic delay. The existence of
reciprocal presumably excitatory chemical synapses between less synchronously active neurons, the amacrine
cells of the retina, was pointed out to me by Paul Fatt, and
reciprocal excitatory chemical synapses also exist in coelenterates w72x. At a meeting of the Neuroscience Research
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
Program, I floated the name ‘‘69 synapses’’, by analogy
with Gray’s type I and II as well as an uncommon sexual
practice, but this nomenclature never caught on.
It may occur to the perceptive reader that synchronizing
a controlling nucleus precisely does not mean that activity
of the effector cells will also be precisely synchronized,
since the conduction distances from the control center can
be quite different. I will return to this point below in
considering the issue of synaptic delay.
5. Fast motor systems
By this time one could generalize that synchronous
activity of electric organs required electrical transmission
Žor a single cell command nucleus.. However, cats do not
have electric organs, and my medical school mammalian
colleagues could easily ignore the data, i.e., the work of
my colleagues and me. To be sure, Purpura invited me to
present the story at a meeting on the thalamus and I argued
that electrical synapses might contribute to thalamic oscillations, although the oscillations are explicable in terms of
recurrent inhibition and spontaneous spike activity w9x. No
one, particularly Eccles, liked the idea. There is still the
possibility of electrical synapses in this system, and evidence for electrical coupling in other pools of synchronously active inhibitory neurons accumulates Že.g.,
Ref. w51x..
Another approach was to look further in fishes, with
which I was familiar, and investigate motor behavior that
involved fast and synchronous activity. The sonic motoneurons of the toadfish were a candidate, since the sonic
muscle, which wraps around the swimbladder, contracts at
the fundamental frequency of the sound, 100–200 Hz, a
frequency comparable to that of many electric organ discharges. This fish was common in Woods Hole and was
being used for its isolated pancreatic islet tissue. Its muscle
had also been studied because of the fast rate of contraction and relaxation. After a modest amount of development, it became possible to record from the sonic motoneurons identified by antidromic stimulation. The cells
were smaller and less accessible than the electromotor
neurons we had previously studied, and I only succeeded
in recording from one cell at a time. However, graded
antidromic stimulation showed short latency graded depolarizations, which identified electrical coupling, and George
Pappas showed gap junctions both between motoneuron
dendrites and between presynaptic fibers and motoneurons
w57x. The antidromic potentials, electrical PSPs, showed
paired pulse facilitation, ascribable to increased degree of
antidromic invasion as a result of depolarization remaining
from the previous response.
During this period I met Hans Lissman, who with
Machin had discovered the discharges of the weakly electric fishes and demonstrated their role in electrolocation.
Although the early anatomists had found the electrogenic
tissue of a number of weakly electric fishes, they were
unaware of the discharges. I cannot remember whether I
actually applied Galvani’s rheoscopic frog preparation to a
weakly electric fish, but it certainly would have detected
the discharges. Hans was a zoologist and knew about many
wonderful animals. Among them was the hatchetfish, which
was thought to fly. It is shaped like a hatchet and has a
large breast bone to which the pectoral fin depressor
muscles attach ŽFig. 4.. Hans had seen it taxi along the
surface, which was much more reasonable in terms of
wing loading. Because of high speed and short latency of
action, the system appeared a promising preparation in
which to prospect for electrical synapses. On one of my
occasional trips to the tropical fish dealers looking for
different species of electric fishes, I saw hatchetfish and
brought a few back to the laboratory for anatomical study.
The medulla proved to have obvious large axoaxonic
synapses between the Mauthner fibers and other large
fibers that it did not take a Cajal to see. The large fibers,
which we called giant fibers, made contact with both
Mauthner fibers, and the giant fibers coursed into the
motor nuclei innervating the pectoral fin depressor muscles. This circuitry suggested that each Mauthner fiber
could excite pectoral fin motoneurons on both sides of the
body. It also suggested that the Mauthner fiber, giant fiber
synapses should be electrical to shorten latency and rectifying to keep one Mauthner fiber from exciting the other
via the giant fibers. Somewhat to my disappointment, Al
Auerbach unequivocally demonstrated that the Mauthner
fiber, giant fiber synapse was chemical w2x. The giant fiber,
motoneuron synapse proved to be electrical, which was
fine, and it was also rectifying, so that this property was
not restricted to the crayfish giant motor synapse w3x. Our
teleological explanation of the rectification was that it
permitted subsets of the motoneurons to be excited by
independent inputs to them in order to generate small
movements without exciting the giant fibers and thereby
all the other motoneurons. Dave Hall using the modern
tracer HRP was able to show that there are gap junctions at
the rectifying synapses that the giant fibers make on the
motoneurons w33x. We now would predict that there are
different connexins in pre- and postsynaptic hemichannels
Mahlon Kriebel and subsequently Henri Korn and I also
investigated oculomotor neurons in puffer and goldfish,
because saccadic eye movements are fast. The cell bodies
were coupled, to which we assigned the task of synchronizing eye movements either for the fast phase of vestibular nystagmus or for eye withdrawal in response to stimulation of cutaneous nerves w41–43,45x. Inputs from the
ipsilateral horizontal canal initiated impulses out in the
dendrites, where we presumed the cells were not coupled
in order to allow graded but rapid saccadic movements.
We also hypothesized that there is electrical coupling in
the saccade generator. We proposed a possible solution to
the problem of generating a synchronous but graded vol-
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
Fig. 4. The Mauthner fiber, pectoral fin circuitry of the hatchetfish. The lower diagrams show side and front views of the fish with the pectoral fins, brain,
spinal cord, and innervation of the pectoral fin depressor muscle ŽM. by anterior ŽaN. and posterior ŽpN. nerves. The upper diagram shows the Mauthner
cells ŽM. giving rise to the Mauthner fibers ŽMF. which decussate; it also shows a single giant fiber of the several that occur on each side. The cell of
origin ŽG. of the giant fiber ŽGF. lies on the side contralateral to its main axon. The GF crosses dorsal to the near MF and forms a single large chemical
synapse Žcs. with it. It then passes ventral to the other MF with which it makes several synapses. It sends a process caudally to the pectoral fin depressor
motoneurons with which it forms rectifying electrical synapses. It also sends a process rostrally which subsequent work showed ends on jaw muscle
motoneurons, probably to close the jaw during fast movement wfrom Ref. w2xx.
ley, which was analogous to an electrophysiological stimulator. One nucleus Žor a transistor or a vacuum tube, which
at that time still existed in stimulators. would generate an
all-or-none synchronous volley using positive feedback,
i.e., in neurons, the spike generating mechanism and electrical coupling of the cells. The synchronous volley would
then generate a rapidly rising PSP in the appropriate
oculomotor neurons that, superimposed on a pre-existing
‘‘excitatory state’’ due to activation of other graded inputs,
would determine what fraction of the neurons were excited
by the rapidly rising PSP Žor in the stimulator analogy,
how large a current flowed through the output stage..
The observation of coupling in the teleost oculomotor
system was particular gratifying, because the many similarities to mammalian oculomotor systems made it more
likely that electrical coupling would be found in them.
Henri looked in the cat and failed to find coupling of
oculomotor neurons. We presumed that coupling at this
level was not necessary in the cat, because there was a
sufficiently synchronous volley from a higher center to
drive the oculomotor neurons to generate a saccade. We
still think it possible that there is coupling of neurons in
the higher center in which saccades are generated.
Mahlon used to go snorkeling at lunch time to net his
own puffers off a nearby beach. Atlantic puffer was becoming fairly rare, since it had been accepted as a food
fish and served in restaurants as sea squab. Many of us
growing up on the East coast knew how good puffer was,
and how easy to remove the meat from the skin. There
were some rumors about poison, but I do not recall their
being connected to the Japanese reality of fugu and
tetrodotoxin. In those days, Americans did not eat ugly
fish such as puffer, skate, and monk fish Ža euphemism for
Lophius piscatorius, an anglerfish.. There is now a fugu
website Ž devoted to sequencing its genome, which has much less intronic DNA
than other vertebrates. Fugu are also raised in mariculture,
although I understand that cultured fugu lack tetrodotoxin,
presumably because a dietary requirement is missing. Do
tetrodotoxin-free fugu sell at a premium or a discount in
Tokyo? Could our own S. maculatus make tetrodotoxin,
given the right diet?
While summering in Woods Hole, Henri found electrically transmitting inputs to primary vestibular neurons in
toadfish w43x, which was an extension of Furshpan’s studies of inputs to the goldfish Mauthner cell w30x. He and
Constantin Sotelo also found electrical coupling and gap
junctions at these synapses in the rat w44x. It was reasonable to think that electrical transmission at this synapse
would shorten reaction time for postural adjustment. Interestingly, this result did not generalize to cats. Perhaps cats
are so big that the small decrease in response latency
provided by electrical transmission at this synapse is not
significant. Then think of an elephant. If there is no
advantage to electrical transmission at this synapse, one
still needs to account for there being chemical transmission. Evolutionary history is a possible explanation and the
last refuge of teleological rascals. Startle circuitry remains
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
interesting as a site where electrical transmission might be
present to speed response, but the advantage is going to be
restricted to small and fast animals.
Considering how rapidly bats can emit distinct cries, we
perfused a bat or two for electron microscopy, but availability questions, and the possibility of rabies, kept us from
getting deeply involved. We thought about hummingbirds,
and Susumu Hagiwara and Ted Bullock captured a few
and measured wing beat frequency. Their work on this
interesting subject to my knowledge never saw the light of
peer review. wThere is nothing in PubMed, which goes
back to just about the time these studies were being done.x
Shosaku Obara investigated the reflex action of the nictitating membrane of the chicken, a remarkably fast blink.
The gross anatomy is intriguing. There are two muscles;
one is attached to the membrane by a long tendon and the
other provides a stirrup through which the tendon makes
an 1808 turn. Thus, the distal part of the tendon moves the
distance that the first muscle contracts plus twice the
distance that the second muscle contracts, and the speed of
membrane movement is nominally three times as fast as
the muscles shorten. Sho never did succeed in getting good
intracellular recordings from the motoneurons, so the question of electrical coupling remains unresolved. This work
only appears in an abstract in the Proceedings of the
XXIVth International Congress of Physiology.
In chicken and most other birds, the eyeballs are almost
in contact back to back. This arrangement makes it difficult to record from the muscles and stimulate the relevant
oculomotor nerves. Owls look forward so that their eyes
are much more favorably placed to get at the eye muscles.
We had a cute burrowing owl around for a long time, but
its cuteness and the fact that owls tend to shift gaze by
moving their heads rather than just their eyes aborted this
6. Electrical versus chemical
The bulk of the initial work on electrical transmission
and synchronization was published in 1966 and 1967. The
basic hatchetfish story came out in 1969. By this time one
could argue Žand I did in too many reviews, e.g., Refs.
w7,10,12,13x., that chemical and electrical synapses could
each do most things required in the nervous system. The
point was not so much that electrical synapses were as
good as chemical synapses, but that one had to be careful
about establishing what the mode of transmission actually
was. There also remained a somewhat adversarial atmosphere. In most instances it was easy to show that inhibition was chemically mediated, but the evidence for excitation was often not compelling. Electrical transmission is
faster, but the latency difference is not so great in warm
blooded animals, and because of postsynaptic input time
constant the measured delay can easily be longer at an
electrical synapse than at a chemical synapse. When one is
dealing with 0.2 ms for a chemical synapse, it is hard to
exclude time to excite and conduction delay in the presynaptic fiber. Chemical synapses are fundamentally unidirectional, but then most single synapses do not excite their
postsynaptic targets in any case. Electrical synapses are
fundamentally bidirectional, unless they are rectifying, and
that may prove to be where they are most useful for
mammals. At that time there were few indications of
plasticity in the electrically coupled systems, although
relatively long-lasting actions could be observed mostly
under artificial conditions. The lack of plasticity may have
been in part a result of working on systems in which
plasticity should not occur, and now numerous instances of
cellular controls of junctional conductance have been found
Že.g., Refs. w18,35,48,58,60x..
There is a contrarian position to be taken about delays
and electrical transmission. As noted above, output cells
may be at quite different distances from a synchronously
firing command nucleus. The general solution to the problem of differing distances is to slow conduction in the
pathway to the more proximal regions of the organ by
making the fibers going to that region have a smaller
diameter Žand perhaps an internodal distance short enough
to reduce conduction velocity w53x andror by making the
fibers take a more devious route w11x. In the electric eel,
for example, the anterior and posterior extremes of the
organ may be separated by over 1 m and at least 10 ms
conduction time. Spinal electromotor neurons, which innervate the electrocytes are activated by spinomedullary
fibers from a relay nucleus in the medulla w53x. Transmission from the descending fibers is electrical, rise times of
the EPSPs are short, and the compensatory delays are
primarily if not exclusively in conduction times in the
preterminal fibers and the peripheral nerves to the electric
organ. Thus, electrical transmission along the axon, by
essentially the same in mechanism as transmission across a
gap junction, provides the delays. Similar mechanisms
may operate in the auditory system where very precise
arrival time comparisons are made to permit source localization w24x. An interesting problem is how the system
wires itself up to achieve the observed precision. It seems
likely that there is feedback in the developmental mechanisms to promote synchronization, but the nature remains
obscure. Eccles raised this question in 1959, but I admit
that at the time I was more interested in the finished
product than how it was made.
7. An aside about evolution
The widely held opinion that electrical transmission is
characteristic of lower forms probably derives from the
large cell systems that were studied in the initial period of
intracellular recording, which hardly constitute a reasonable sample. There may be a kernel of truth in the idea,
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
since synaptic delay is shorter at mammalian body temperature and this advantage of electrical transmission is less
important. With respect to primitiveness, I have argued
that unicellular organisms evolved the basic machinery of
chemical transmission for release of and response to chemicals, but have no functional equivalent of electrical
synapses. Thus, gap junctions are the more advanced form
of transmission. This view is strengthened by the recent
findings that Ecdysozoan and vertebrate gap junctions are
formed by different gene families. It is a good bet that
invertebrates of the Deuterostome line ŽEchinoderms, Ascidians, Chordates. will also have connexin based gap
junctions, and ascidian blastomeres have voltage dependent gap junctions very similar to those of amphibians
Žpublished only in abstract form w40x.. The term ‘‘innexins’’, coined as a contraction of invertebrate connexins,
has been proposed to denote the Ecdysozoan family of gap
junction proteins. This term will prove something of a
misnomer, in the likely event that connexins are found in
invertebrate Deuterostomes or even Lophotrochozoa Žannelids and molluscs among others.. Since homologs of
mammalian glutamate receptors are found in Drosophila,
it is clear that glutamatergic transmission is more primitive, or at least phylogenetically older, than gap junction
mediated communication in either or both the vertebrates
and arthropods. Nice looking gap junctions are seen in
coelenterates diverging before either bilaterian group; it
will be of interest to determine if coelenterate gap junctions are encoded by either of the two described gap
junction gene families. As a further indication of the
advanced nature of gap junctional communication, many
of the proteins recently implicated in neurotransmitter
release have homologs involved in secretion in yeast w23x,
but homologs of connexins have not been reported outside
of vertebrates w54x.
Septate junctions are found in the Protostome line
ŽEcdysozoa and Lophotrochozoa. and also in the Deuterostome line and apparently serve a similar function to tight
junctions. Although they are prominent in Echinodermata,
only a few ‘‘septate-like’’ junctions have been described in
vertebrates, at the initial segment of Mauthner cells and of
cerebellar Purkinje cells where there is electrical inhibition
and also in the testis between Sertoli cells w27x. Tight
junctions have largely replaced septate junctions in epithelia. There is homology between caspr, a molecule at the
axon, Schwann cell junction in the perinodal region, and a
neurexin in Drosophila that participates in formation of
septate junctions w6x. In the vertebrate electrical inhibitory
synapses the septate-like junction may be serve a barrier
function to increase access resistance from initial segment
to surrounding tissues. In myelinated nerve and Sertoli
cells it may also be acting as a barrier. It is entertaining
that the most important electrical synapse molecules in
vertebrates, the connexins, are not homologous with the
gap junction proteins of the Ecdysozoan line, whereas
these other molecules, which may be found at the rela-
tively rare electrical inhibitory synapses, have Ecdysozoan
8. Romance in academia
Gunther Stent has said that a research field has romantic
and academic phases. In a romantic phase, there are new
discoveries and whole new vistas open up. His prime
example was the discovery of DNA and the genetic code.
Intracellular recording opened a romantic phase in neurophysiology, now a little used term, and I remember meetings of the American Physiological Society at which one
could go to every paper involving intracellular recording
Žor of the Society for Neuroscience where one could see
all the posters involving patch clamping.. As the number
of impulses and number of neurons increased, the field
entered an academic phase, where knowledge was being
filled in. The endeavor was valid and important for further
work, but great new dishabituating insights were not immediately forthcoming. Then cloning and patch clamping
opened a new romantic phase of burgeoning excitement.
We are now well into a phase of brute force science, in
which it is possible to sequence entire genomes and with
gene chips determine all the changes in gene expression
and protein levels associated with a given physiological or
pathological response. It is hard to consider this direction
romantic or even hypothesis driven, other than the belief
that something interesting must be happening and will be
found. Going on a fishing expedition is rarely fundable at
the NIH, even when it is clear that there are fish in these
here waters. Major funding is going to genome sequencing; draining the lake may not be a clever approach to
finding fish, but it certainly is effective.
I felt romantically involved with electrical transmission
in the 1960s, but in my view the field was in an academic
phase through the seventies. There had been a few instances of electrical transmission demonstrated in mammals, e.g., in the mesencephalic trigeminal nerve nucleus
and the inferior olive w4,47x. There were a few morphological reports of gap junctions between mammalian neurons.
Particularly gratifying to me were the dendrodendritic gap
junctions in the sensory cortex of the monkey, a primate
no less w62x, as well as in the olfactory bulb and hippocampus w61x. Still, the data w74x came slowly in that fixation of
the CNS for electron microscopy was difficult, Lucifer
Yellow, neurocytin, and other tracers were not yet available, and neurons could not be visualized in brain slices.
In the early 1980s there were exciting new findings of
gating at gap junctions both by application of transjunctional voltage and by cytoplasmic acidification w34,64x.
The recording of single channels by Neyton and Trautman
w55x through use of patch clamping of small high resistance
cells was inspirational if confusing because of slow opening and closing of single channels that often occurred
interspersed with faster transitions like those we had come
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
to expect from single channels. Slow transitions have now
been seen in many cell and junction types, and are ascribable to transitions through substates differing little in
conductance, e.g., Ref. w65x. When single channel recording was combined with exogenous expression of cloned
connexins, wildtype and modified by site directed mutagenesis, it was a romantic moment, which of course is
leading into the academic enterprise of understanding the
structure and function of connexins.
Over my scientific lifetime there have been many
changes. I grew up with NIH, so have no personal understanding of how it was before. After the Žsecond World.
War the US Congress was persuaded to support the health
sciences broadly speaking, and, although I am in a position
of conflict of interest, I believe that it was good for the
country and humanity, as well as me. A memorable quote
from Charles Wilson, Secretary of Defense under Eisenhower, when testifying before Congress: he said that
‘‘Basic research is where you don’t know what you are
doing’’. He was of course right in one sense, because you
would not have to do the research if you knew the
outcome. Hypothesis driven research means you have an
idea about the outcome and is all very well. I do have a
genuine distaste for inventing history in the way some
investigators formulate clever hypotheses after they have
made fortuitous observations. It is scientific fraud in terms
of method, even if the actual data are real.
I believe Wilson would have supported the human
genome project. But in spite of him there was a time that I
could write in a grant application that the results had no
direct relevance to human health, but that they were important for general understanding. And get the grant. I still
believe that that is the relevance of most of my work, but I
would not state it so baldly in seeking NIH funding. Over
the years, in response to budgetary exigencies we have
become more skilled in giving a potential clinical significance to our work. For example, acidosis following cardiac
arrest would decrease junctional conductance between cardiocytes, although pH dependence of junctional conductance was demonstrated in blastomeres. Electrical coupling
of neurons via gap junctions may be important in seizure
generation, a nice idea with little direct evidence. Loss of
coupling may lead to reduced growth control and promote
Žnot initiate. carcinogenesis. These few examples are typical of the not very strongly based arguments for the
importance of gap junctions. Thus, it gave great pleasure
when the first connexin disease was reported w22x, although
the relatively mild nature of X-linked Charcot-Marie-Tooth
disease and restriction to peripheral nerve had to disappoint some investigators with large investments in Cx32.
Consider that Cx32 had not even been described in nerve
prior that report. More recently, mutations in Cx26 have
been shown to cause deafness w15x. It is virtually certain
that other connexin diseases will appear, because it is
unthinkable that the other connexins are not important and
unlikely that all mutations in other connexins will be
embryonic lethal. It has been difficult to predict what a
gene knockout will do; one would not have predicted CMT
or deafness as the presenting manifestations of Cx32 and
Cx26 knockouts. An interesting problem remains, not satisfactorily explained to my knowledge. How is expression
selected for in tissues that show no obvious effect of loss
of a gene product that they strongly express and when a
major decrease in fitness is associated with loss of expression of this gene in another tissue?
The first targeted disruption of connexins was a romantic moment. The effort becomes more academic as more
genes are targeted. Conditional knockouts are romantic and
promise to avoid the developmental and strain differences
that plague mouse knockouts. Knockout, knockin is romantic and promises to bring understanding to the functional differences between connexins and between their
regulated expression when the proteins can substitute for
one another. It is likely to become academic as more and
more mutations are evaluated. Knockin of mutant connexins will allow validation of the causes of genetic connexin
diseases, but would become academic if used to evaluate
the more that 180 known mutations in Cx32.
To me the new findings of electrical transmission in
mammals are romantic, like an encounter with a former
lover for whom one has carried a torch for many years.
The cloning of connexins now permits in situ hybridization
and antibody labeling, and expression of connexins is
common in central neurons. A laborious combination of
confocal light microscopy and freeze fracture electron
microscopy has revealed an unexpectedly Žand for me
delightfully. high incidence of synapses with both gap
junctions and morphological characteristics of chemical
synapses in rat spinal cord w59x. There is a caveat about
morphological approaches. We all know that RNA may
not make a protein and a protein may not function, but we
have been comfortable with anatomically described chemical synapses and gap junctions as indicative of function.
However, presynaptic vesicles, which define an active
zone, are also found at axosomatic and axodendritic
synapses where electrophysiological findings indicate that
transmission is purely electrical w21,44,57x. In fact, it appears that all axodendritic and axosomatic synapses with
gap junctions also have active zones, i.e., they are morphologically mixed synapses. Dual electrical and chemical
transmission is not that common w25,46,52x. Now come
silent synapses that may not express receptors or release
transmitter Že.g., Refs. w49,50x.. The presynaptic vesicles
and densities at functionally electrical synapses may be
involved in membrane recycling of surface proteins or take
up of extracellular factors. Conversely, correlation of the
number of gap junction channels at club endings on the
Mauthner cell with junctional conductance suggests that
most of the channels are closed and that gap junctional
area is not a good measure of junctional conductance w66x.
Feliksas Bukauskas and numerous collaborators in and
outside of our group in still unpublished work find that
M.V.L. Bennettr Brain Research ReÕiews 32 (2000) 16–28
Cx43 labeled with a green fluorescent protein must form
quite sizable plaques before even a single channel starts to
open. Also with respect to predictive value, single channel
conductance of junctions formed by cloned connexins can
vary by an order of magnitude w68x.
My summary conclusion as of now is that gap junctions
constitute a small but respectable minority of synapses in
the mammalian brain, as well as in the brains of ‘‘lower’’
forms. This is a cold calculation rather than a romantic
fantasy, and we will progress inevitably through new
romantic and academic periods. I will savor each romance,
work hard as the relationship matures and eagerly but
patiently await the next one.
This work depended on numerous colleagues most of
whose names can be found in the reference list; I am
deeply indebted to them. Funding came from many NIH
and NSF grants over the years, initially to Harry Grundfest. A major support for 26 years has been NS-07512. I
am the Sylvia and Robert S. Olnick Professor of Neuroscience.
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