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Excessive discharge alone does not necessarily cause a seizure. Synchronization of a network of neurons is involved. Therefore, how synchronization occurs becomes important to consider. There are many ways neurons can synchronize. In 1964, Matsumoto and Ajmone-Marsan found that the electrographic events recorded at the cortical surface during seizures corresponded to paroxysmal depolarization shifts (PDS) of cortical pyramidal cells occurring synchronously (Matsumoto and Marsan, 1964). These studies led to efforts to understand how neurons begin to fire in concert when normally they do not. Glutamatergic interconnections are one example of a mechanism that can lead to synchronization. Indeed, studies of the PDS suggested that the underlying mechanism was a ‘giant’ excitatory postsynaptic potential, although it was debated widely at that time if this was the only cause (Johnston and Brown, 1984). Thus, pyramidal cells of cortex are richly interconnected to one another by glutamatergic synapses. Gap junctions on cortical neurons are another mechanism for synchronization. Gap junctions allow a low-resistance pathway of current flow from one cell to another, so that coupled neurons are rapidly and effectively synchronized. It was thought that gap junctions were rare, so it was unlikely that they could play a major role, but further study led to the appreciation that even a few gap junctions may have a large impact on network function (Traub et al., 2004). Another mechanism of synchronization involves, paradoxically, inhibition.

Many GABA-ergic neurons that innervate cortical pyramidal cells, such as the cell type that controls somatic inhibition (the basket cell), make numerous connections to pyramidal cells in a local area. Therefore, discharge of a single interneuron can synchronously hyperpolarize a population of pyramidal cells. As GABA-ergic inhibition wanes, voltage-dependent currents of pyramidal cells become activated. These currents, such as T-type calcium channels and others, are relatively inactive at resting potential, but hyperpolarization relieves this inhibition. The result is a depolarization that is synchronous in a group of pyramidal cells (Scharfman, 2007).

Some of the changes that develop within the brain of individuals with epilepsy also promote synchronization. Such changes are of interest in themselves because they may be one of the reasons why the seizures are recurrent. These changes include growth of axon collaterals of excitatory neurons, typically those that use glutamate as a neurotransmitter and are principal cells. An example is the dentate gyrus granule cell of hippocampus. In animal models of epilepsy and in patients with intractable temporal lobe epilepsy (TLE), the axons of the granule cells develop new collaterals and the new collaterals extend for some distance. They do not necessarily terminate in the normal location but in a novel lamina, one that contains numerous granule cell dendrites. Electron microscopy has shown that the new collaterals innervate granule cell dendrites, potentially increasing recurrent excitatory circuits. Some argue that recurrent inhibition increases as well as recurrent excitation, but the fact remains that new synaptic excitatory circuits develop that are sparse or absent in the normal brain (Nadler, 2003; Sloviter et al., 2006). The resultant ‘synaptic reorganization’ not only can support synchronization, potentially, but it also illustrates how the plasticity of the nervous system may contribute to epileptogenesis.