Mind the gap

Soon after the discovery of the neuron as the basic functional unit of the nervous system, a model of how nerve cells function emerged. According to this model - the neuron doctrine - the cell body integrates nervous impulses received by the dendrites, and generates an output, in the form of a train of impulses with a specific pattern, which is propagated along the axon. When these impulses reach the nerve terminal, they elicit the release of neurotransmitters, which diffuse across the synapse and bind to receptors embedded in the dendrite membrane of the adjacent cell.

This model soon became generally accepted, because it neatly explains how something as simple as a nervous impulse can convey so many different types of information: it is not the impulse itself that is important, because the impulses generated by the thousands of different cell types in the brain are basically the same. Rather, what matters is the connections made by the cell generating the impulses, as well as the pattern of the impulses generated.

But things are never as simple as they first seem, especially when it comes to the brain, which is the most complex object in the known universe. So, although the neuron doctrine remains useful, new evidence suggests that it is inadequate. For example, two papers published earlier this year in Nature Neuroscience provide evidence that neurotransmitters can be released from axonal sites far away from the nerve terminal. And now, a new study suggests that a hitherto overlooked type of inter-neuronal communication may be vital to normal brain function, and could also be involved the abnormal electrical activity associated with epilepsy.

Conventionally, neuronal signalling has always been thought of as involving the transmission of chemical signals across synapses. Gap junction signalling, however, involves the direct flow of electrical currents or chemicals between cells. These movements take place via proteins called connexins that are embedded in the nerve cell membrane.

Thus, gap junctions allow for the electrical and chemical coupling of neighbouring cells. They are found, for example, in the heart, where they propagate the electrical signals that elicit the rhythmic contractions of the cardiac muscle. And, of course, gap junctions are found in the brain; here, they are thought to mediate communication between glial cells, and to play a only minor role in transmitting inhibitory signals between neurons.

From the findings of a number of studies, it has been predicted that gap junctions may exist between axons of excitatory neurons. For example, electrical activity has been observed in cortical cells cultured in a medium containing inhibitors of neurochemical transmission; and it has been shown that coloured dyes can spread between pyramidal neurons from various regions of the hippocampus. However, until now there has been no other evidence that gap junction signalling takes place between excitatory neurons in the cerebral cortex.

The new study, led by Farid Hamzei-Sichani, of the SUNY Downstate Medical Center in Brooklyn, New York, provides the first anatomical evidence that gap junctions couple the axons of excitatory cells in the brain. The findings are to be published later this week in the Proceedings of the National Academy of Sciences.

Hamzei-Sichani et al investigated the granule cells in the dentate gyrus of the hippocampus. These cells have axons called mossy fibers, which were named as such by Santiago Ramon y Cajal because of an abundance of dendritic spines, known as thorny excrescences. These spines are found along the entire length of the fibers, and give them a mossy appearance.

Mossy fibers enter the CA3 hippocampal region, where they form synapses with pyramidal cells. The mossy fibers are excitatory - they release glutamate, which elicits increased activity in the pyramidal cells. And they are highly complex - each forms dozens of synapses with a single pyramidal cell.

Using freeze fracture electron microscopy to magnify hippocamal tissue from rats up to 30,000 times, the researchers found numerous examples of gap junctions between adjacent mossy fibers. They predict that they may give rise to very-high frequency oscillations of electrical activity in the brain by amplifying the signals generated by the granule cells.

In epilepsy, seizures are caused when abnormal electrical activity spreads from a focus in the brain to surrounding tissue. It is known that the onset of a seizure is accompanied by very-high frequency (>100Hz) of electrical activity at the focus. This is generally believed to occur as a result of either increased excitatory chemical transmission or decreased inhibition.

However, Roger Traub, the senior author of the paper, has hypothesized that  it is the electrical coupling of excitatory cells via gap junctions leads to the abnormal activity associated with epileptic seizures. The new study provides some evidence for Traub's theory, and also suggests that coupling of excitatory cells via gap junctions may be necessary for normal brain function. Some researchers also believe that excessive excitatory signalling via gap junctions may play a role in psychoses and other mental illnesses.

Traub's theory has proven to be controversial, and it remains to be seen whether or not gap junctions do in fact play a role in epileptic seizures. But the idea that neurons use gap junctions for signalling doesn't seem so radical, because in recent years it has become clear that cell-to-cell signalling in the brain is far more complex than was previously thought. It is now known, for example, that glial cells - which were once thought to merely provide support for neurons - can actively communicate with each other and with neurons. So it would not be too surprising if it was found that neurons use gap junctions to signal to each other.