Too hot! As our fingertips graze the hot stove, their thermal receptors sound an alarm. The message races at 300 kilometers an hour through the nervous system to the brain, where it gets immediate attention. The muscles receive an order to pull those fingers away from the surface. Such messages–encoded as electrical impulses–constantly stream through our nervous system. They not only prevent us from burning our fingers on the hot stove but also enable our very survival. A century ago some neurophysiologists believed that these impulses traveled through unbroken paths, in a system akin to the electric cables or water pipes in a home. Others argued that every neuron was an island unto itself. Today we know that both camps are partly right [see “Beyond the Neuron Doctrine,” by R. Douglas Fields; Scientific American Mind, June/July]. Most neurons communicate via messenger compounds called neurotransmitters that travel across gaps, or chemical synapses, between the cells. Some neurons, however, also have physically continuous, pipelike connections to other cells, which scientists call electrical synapses. Electric Speed Although chemical synapses have gotten most of the attention, evidence existed for the electric alternative as long ago as the middle of the 20th century. In 1957 neurophysiologists Edwin Furshpan and David Potter, now both professors emeritus at Harvard Medical School, first reported finding direct electrical conduction of signals in the giant motor neurons of crayfish. That year Michael V. L. Bennett, now at the Albert Einstein College of Medicine, described the same phenomenon in his work with the toxin produced by the blowfish, the (sometimes deadly) delicacy fugu beloved in Japanese cuisine. Further research on electrical synapses remained almost as exotic as blowfish preparation for a long time. Only in the past few years has science unraveled the cellular workings at the molecular level. The advantage of electrical synapses over their chemical counterparts is obvious: by omitting neurotransmitter middlemen, electrical synapses conduct impulses from one neuron to the next at far higher speeds. Chemical synapses secrete neurotransmitters, which must cross the synaptic gap to deliver their message. The entire process takes about half a millisecond. That may seem fast, but for many physiological processes–such as the flight reflex of the blowfish, during which it instantaneously flips its tail to escape predators–it would be too slow for survival. In such cases, electrical synapses are at work, delivering their signals almost without delay. Synapse Secrets How do they work? Linked membrane proteins form a conduit between neurons. In the middle there is a pore through which positively charged particles, or ions, can flow from one cell into the next. There, by means of a kind of controlled short circuit, they cause an impulse called an action potential, which can then be sent onward by the next cell. Electrical synapses appear to play a role in the synchronous firing of large sets of neurons, as was discovered independently in 2001 by Barry Connors of Brown University and Hannah Monyers lab at the University of Heidelberg in Germany. The researchers found that in mice lacking a gene for creating electrical synapses, nerve cells could not fire rhythmically in the 30- to 60-hertz range. Furthermore, electrical synapses were especially prominent in certain interneurons (which communicate only with other neurons) in the cerebral cortex and hippocampus. These cells, in turn, inhibit, or help to regulate, higher-level nerve networks that process sensory perception and control muscle movements. Apparently, the interneurons that are connected by electrical synapses filter the incoming flood of data by transforming the stimuli into rhythmic discharges, and by then propagating these rhythms over large distances. The electrical synapses thus generate the rapid spread of rhythmic activity, activating different brain regions almost simultaneously. The electrical synapses are known as gap junctions because of their appearance under an electron microscope. These fast contacts are concentrated in certain regions, where the precise synchronization of large groups of cells is vital. Gap junctions deliver, for instance, the electric stimuli that enable the coordinated contraction of the heart. They also are found in the olfactory bulb, in the center of the brain stem, in the retina and among the pyramidal cells in the hippocampus, where they are involved in a special type of memory storage. Electrical synapses fast communication is important during embryonic development. In the developing rodent brain, gap junctions couple together undifferentiated stem cells, the precursors of more mature neurons. These synapses are not yet capable of synchronizing electrical activity, because the precursor cells cannot fire. Instead they are involved in controlling cell division, as Arnold Kriegstein, now at the University of California, San Francisco, showed in 2004. When the researchers inhibited the gap-junction coupling of the embryonic cells, cell division went completely out of control. The regulated increase in the number of precursor cells is crucial to brain maturation, because the cells must move from the fluid-filled inner zones of the brain into the surrounding tissue in groups that later develop into individual brain regions. When the neuronal precursor cells are uncoupled, the consequences are fatal. After birth, electrical synapses continue to play a key role in brain development. In rats these cell connections exist between virtually all neurons during the first two weeks after birth. As these cell connections drop in number, chemical synapses increase, as Karl Kandler, now at the University of Pittsburgh, and the late Lawrence C. Katz of Duke University described in 1998. Their spontaneous development may help to sculpt immature circuits. As neuronal circuits mature and create their own chemical synapses to process sensory experiences, most of the gap junctions gradually disappear. The postnatal boom for electrical synapses reflects the fact that gap junctions represent an ancient principle of cell communication. Even simple multicellular organisms, such as sea squirts and sponges, have gap junctions. It is striking that electrical synapses appear very early on in the developing nervous systems of mammals, whereas their chemical counterparts do not show up until after birth. Apparently, the electrical connections are meant to keep communication going between neurons until the final, chemical connections are established. As the electrical synapses pass the baton to their chemical siblings, they clear the way for the construction of the complex brain. Gaps Gone Wrong Flaws in gap junctions appear to play a role in many neurological disorders. For example, in epileptic seizures huge populations of neurons spanning several brain regions fire synchronously [see “Controlling Epilepsy,” by Christian Hoppe; Scientific American Mind, June/July]. All the evidence speaks for the involvement of electrical synapses: they are found in a network of neurons that is normally responsible for inhibiting the overlying nervous system in which the attack takes place; scientists have observed epilepsylike discharges by groups of neurons that are electrically coupled in isolated areas of the brain; and in 2004 researchers led by Christophe Mas of the University of Geneva discovered that in an inherited form of epilepsy, the gene that codes for the main protein in electrical synapses is altered. Given the recent findings, it may be possible in the future to treat certain forms of epilepsy with drugs that reduce the excitability of electrical synapses. Gap junctions may also be involved in the aftermath of strokes. Neurologists have long wondered why the size of the damaged area continues to increase for many hours after the stroke event, far beyond the region originally affected. The reduction of this penumbra, which surrounds the original site of destroyed tissue like a halo, would constitute an enormous advance in the treatment of stroke. The key to solving penumbra damage most likely lies among the astrocytes, non-neuronal cells named for their starlike shape. Like nurses, these cells make sure the neurons around them receive a balanced diet of ions, neurotransmitters and growth factors. The astrocytes are themselves coupled to each other through countless thousands of gap junctions, making an intensive exchange of molecules possible. Thus, this network could also distribute the harmful metabolic products resulting from the massive death of brain tissue, thereby damaging cells not killed directly by the stroke. Whether research into these direct nerve cell contacts will provide promising new therapies remains to be seen. What is certain is that the electrical synapses have lost their wallflower status and are now taking their rightful place as fascinating and important objects of research.
Such messages–encoded as electrical impulses–constantly stream through our nervous system. They not only prevent us from burning our fingers on the hot stove but also enable our very survival.
A century ago some neurophysiologists believed that these impulses traveled through unbroken paths, in a system akin to the electric cables or water pipes in a home. Others argued that every neuron was an island unto itself. Today we know that both camps are partly right [see “Beyond the Neuron Doctrine,” by R. Douglas Fields; Scientific American Mind, June/July]. Most neurons communicate via messenger compounds called neurotransmitters that travel across gaps, or chemical synapses, between the cells. Some neurons, however, also have physically continuous, pipelike connections to other cells, which scientists call electrical synapses.
Electric Speed Although chemical synapses have gotten most of the attention, evidence existed for the electric alternative as long ago as the middle of the 20th century. In 1957 neurophysiologists Edwin Furshpan and David Potter, now both professors emeritus at Harvard Medical School, first reported finding direct electrical conduction of signals in the giant motor neurons of crayfish. That year Michael V. L. Bennett, now at the Albert Einstein College of Medicine, described the same phenomenon in his work with the toxin produced by the blowfish, the (sometimes deadly) delicacy fugu beloved in Japanese cuisine. Further research on electrical synapses remained almost as exotic as blowfish preparation for a long time. Only in the past few years has science unraveled the cellular workings at the molecular level.
The advantage of electrical synapses over their chemical counterparts is obvious: by omitting neurotransmitter middlemen, electrical synapses conduct impulses from one neuron to the next at far higher speeds. Chemical synapses secrete neurotransmitters, which must cross the synaptic gap to deliver their message. The entire process takes about half a millisecond. That may seem fast, but for many physiological processes–such as the flight reflex of the blowfish, during which it instantaneously flips its tail to escape predators–it would be too slow for survival. In such cases, electrical synapses are at work, delivering their signals almost without delay.
Synapse Secrets How do they work? Linked membrane proteins form a conduit between neurons. In the middle there is a pore through which positively charged particles, or ions, can flow from one cell into the next. There, by means of a kind of controlled short circuit, they cause an impulse called an action potential, which can then be sent onward by the next cell.
Electrical synapses appear to play a role in the synchronous firing of large sets of neurons, as was discovered independently in 2001 by Barry Connors of Brown University and Hannah Monyers lab at the University of Heidelberg in Germany. The researchers found that in mice lacking a gene for creating electrical synapses, nerve cells could not fire rhythmically in the 30- to 60-hertz range. Furthermore, electrical synapses were especially prominent in certain interneurons (which communicate only with other neurons) in the cerebral cortex and hippocampus. These cells, in turn, inhibit, or help to regulate, higher-level nerve networks that process sensory perception and control muscle movements. Apparently, the interneurons that are connected by electrical synapses filter the incoming flood of data by transforming the stimuli into rhythmic discharges, and by then propagating these rhythms over large distances. The electrical synapses thus generate the rapid spread of rhythmic activity, activating different brain regions almost simultaneously.
The electrical synapses are known as gap junctions because of their appearance under an electron microscope. These fast contacts are concentrated in certain regions, where the precise synchronization of large groups of cells is vital. Gap junctions deliver, for instance, the electric stimuli that enable the coordinated contraction of the heart. They also are found in the olfactory bulb, in the center of the brain stem, in the retina and among the pyramidal cells in the hippocampus, where they are involved in a special type of memory storage.
Electrical synapses fast communication is important during embryonic development. In the developing rodent brain, gap junctions couple together undifferentiated stem cells, the precursors of more mature neurons. These synapses are not yet capable of synchronizing electrical activity, because the precursor cells cannot fire. Instead they are involved in controlling cell division, as Arnold Kriegstein, now at the University of California, San Francisco, showed in 2004. When the researchers inhibited the gap-junction coupling of the embryonic cells, cell division went completely out of control. The regulated increase in the number of precursor cells is crucial to brain maturation, because the cells must move from the fluid-filled inner zones of the brain into the surrounding tissue in groups that later develop into individual brain regions. When the neuronal precursor cells are uncoupled, the consequences are fatal.
After birth, electrical synapses continue to play a key role in brain development. In rats these cell connections exist between virtually all neurons during the first two weeks after birth. As these cell connections drop in number, chemical synapses increase, as Karl Kandler, now at the University of Pittsburgh, and the late Lawrence C. Katz of Duke University described in 1998. Their spontaneous development may help to sculpt immature circuits. As neuronal circuits mature and create their own chemical synapses to process sensory experiences, most of the gap junctions gradually disappear.
The postnatal boom for electrical synapses reflects the fact that gap junctions represent an ancient principle of cell communication. Even simple multicellular organisms, such as sea squirts and sponges, have gap junctions. It is striking that electrical synapses appear very early on in the developing nervous systems of mammals, whereas their chemical counterparts do not show up until after birth. Apparently, the electrical connections are meant to keep communication going between neurons until the final, chemical connections are established. As the electrical synapses pass the baton to their chemical siblings, they clear the way for the construction of the complex brain.
Gaps Gone Wrong Flaws in gap junctions appear to play a role in many neurological disorders. For example, in epileptic seizures huge populations of neurons spanning several brain regions fire synchronously [see “Controlling Epilepsy,” by Christian Hoppe; Scientific American Mind, June/July]. All the evidence speaks for the involvement of electrical synapses: they are found in a network of neurons that is normally responsible for inhibiting the overlying nervous system in which the attack takes place; scientists have observed epilepsylike discharges by groups of neurons that are electrically coupled in isolated areas of the brain; and in 2004 researchers led by Christophe Mas of the University of Geneva discovered that in an inherited form of epilepsy, the gene that codes for the main protein in electrical synapses is altered. Given the recent findings, it may be possible in the future to treat certain forms of epilepsy with drugs that reduce the excitability of electrical synapses.
Gap junctions may also be involved in the aftermath of strokes. Neurologists have long wondered why the size of the damaged area continues to increase for many hours after the stroke event, far beyond the region originally affected. The reduction of this penumbra, which surrounds the original site of destroyed tissue like a halo, would constitute an enormous advance in the treatment of stroke.
The key to solving penumbra damage most likely lies among the astrocytes, non-neuronal cells named for their starlike shape. Like nurses, these cells make sure the neurons around them receive a balanced diet of ions, neurotransmitters and growth factors. The astrocytes are themselves coupled to each other through countless thousands of gap junctions, making an intensive exchange of molecules possible. Thus, this network could also distribute the harmful metabolic products resulting from the massive death of brain tissue, thereby damaging cells not killed directly by the stroke.
Whether research into these direct nerve cell contacts will provide promising new therapies remains to be seen. What is certain is that the electrical synapses have lost their wallflower status and are now taking their rightful place as fascinating and important objects of research.
