Changes in GABA Signaling

Epilepsy describes a set of diseases characterized by hyperexcitability and synchronous firing of large groups of neurons. Although there are many different kinds of epilepsy, temporal lobe epilepsy (TLE) is the most common type in adults and is often difficult to resolve. TLE seizures usually begin in the hippocampus and spread to involve large parts of the brain. Genetic mutations, injury, or tumors can all result in TLE. TLE usually causes extensive changes within the hippocampus, including the death of subsets of neurons, neuritic sprouting, and sclerotic lesions. The hyperexcitability characteristic of TLE suggests that this disease compromises GABAergic inhibition.

GAD levels increase in parts of the TLE hippocampus, but GABA levels decrease. Since GAD increases as a result of many types of injury, the changes observed in TLE may not serve to provide more GABA for signaling. Instead, the increase may reflect a general cellular response to injury, and the resultant GABA may be diverted to the GABA shunt to provide energy for the cell.

Hyperexcitability could reflect the loss of GABA neurons, but the neurons that die in TLE are mainly excitatory cells. Only a small subset of GABAergic neurons, which coexpress somatostatin, is lost. Several hypotheses address the compromised inhibitory capability of the TLE hippocampus. One possibility is that the excitatory inputs to some GABAergic neurons are lost, thus decreasing their inhibitory signaling. Another suggestion is that some GABAergic neurons lose their targets and redirect their outputs to many cells. The result is that one inhibitory cell now drives many excitatory cells, causing the synchronized firing that is a hallmark of TLE. A third hypothesis suggests that GABAergic neurons redirect their output to other GABAergic neurons, thus providing a net excitatory output relative to the normal state.

The multitude of changes within the TLE hippocampus may mean that one comprehensive treatment approach is impossible. Although GABA neurons are mainly intact, changes in connections may either increase or decrease net inhibition. GAD levels are increased, GABA receptors are increased in some cells but decreased in others, the GABA transporter is decreased only in some areas of the hippocampus, and overall GABA is decreased. Nonetheless, many of the drugs that are effective for treating TLE increase GABA action through potentiating GABAA receptors (thus creating a more powerful response to endogenous GABA) or by interfering with GAT1 or GABA-T to increase available GABA.

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