Inhibitory Neurotransmission

The main inhibitory transmitter in the brain is y-aminobutyric acid (GABA). GABA is synthesized from glutamate in the presynaptic terminal by action of the enzyme glu-tamic acid decarboxylase (GAD), which requires pyridoxine (vitamin B6) as a cofactor (Fig. 2A). Influx of calcium ions (Ca2+) caused by depolarization of the terminal of the inhibitory neuron causes vesicles to release GABA into the synaptic cleft. GABA diffuses across the cleft and binds to its receptors (GABAA), and this sequence opens a pore or channel through which chloride ions (Cl-) enter the neuron. This Cl- influx increases the negative charge inside the postsynaptic neuron, hyperpolarizing it. The resultant change in membrane potential is called an inhibitory postsynaptic potential (IPSP) (Fig. 3). An IPSP reduces firing of the postsynaptic neuron by temporarily keeping the membrane potential away from its firing threshold.

Another type of GABA receptor (GABAb) also exists. GABAb receptors are located both presynaptically and postsynaptically. Activation of presynaptic GABAB receptors reduces transmitter release, which could have an anti- or proepileptic effect, depending on whether the neuron is excitatory or inhibitory. Activation of postsynaptic GABAB receptors elicits a long-lasting IPSP mediated by a G protein that opens a potassium ion (K+) channel. The role of GABAb receptors in epilepsy is being explored (13).

After GABA is released, it is rapidly taken up by the presynaptic neuron and degraded by the action of the catabolic enzyme GABA transaminase. Obviously, a reduction of any component of GABA synthesis, release, or binding would favor excitation and predispose to epileptic firing. Conversely, enhancing GABA function or decreasing its degradation would be a logical approach to restraining neuronal hyperexcitability. Several AEDs act on various aspects of the GABA system (see Section 8.).

Like all neurotransmitter receptors, GABA receptors are composed of many different subunits, each of which is under distinct genetic control. This allows for a wide diversity of GABA receptor types, which may differ from each other only in one or two sub-units. Nevertheless, this subunit multiplicity creates a huge functional diversity in inhibitory control; different subunit combinations may confer differential functions and degrees of pharmacologic sensitivity on the receptor. In addition, the subunit composition may change during development. At different stages of brain maturation, GABA can mediate depolarization, hyperpolarization, or trophic (growth-regulating) actions (14). Obviously, this wide diversity could mediate function-specific pharmacologic modulation, which could play a significant role in seizure suppression at different ages or in different regions of the brain.

Fig. 3. Normal neuronal firing: left, schematic of neuron with one excitatory (E, open) and one inhibitory (I, solid) input; right, membrane potential, beginning at resting potential (-70 mV). Activation of E leads to graded EPSPs: a small one (dotted curve), and a larger one (solid line) that reaches threshold (approx -40 mV) for an action potential. The action potential is followed by an afterhyperpolariza-tion (AHP), the magnitude and duration of which determine when the next action potential can occur. Activation of the inhibitory input (I) causes an IPSP (dashed curve). Inset magnified portion of the neuronal membrane as a lipid bilayer with interposed voltage-gated Na+ and K+ channels; the direction of ion fluxes during excitatory activation is shown. After firing, the membrane bound sodium-potassium pump (Na+, K+-ATPase) and star-shaped astroglial cells help to restore ionic balance. (Modified with permission of the American Academy of Pediatrics from ref. 58.)

Fig. 3. Normal neuronal firing: left, schematic of neuron with one excitatory (E, open) and one inhibitory (I, solid) input; right, membrane potential, beginning at resting potential (-70 mV). Activation of E leads to graded EPSPs: a small one (dotted curve), and a larger one (solid line) that reaches threshold (approx -40 mV) for an action potential. The action potential is followed by an afterhyperpolariza-tion (AHP), the magnitude and duration of which determine when the next action potential can occur. Activation of the inhibitory input (I) causes an IPSP (dashed curve). Inset magnified portion of the neuronal membrane as a lipid bilayer with interposed voltage-gated Na+ and K+ channels; the direction of ion fluxes during excitatory activation is shown. After firing, the membrane bound sodium-potassium pump (Na+, K+-ATPase) and star-shaped astroglial cells help to restore ionic balance. (Modified with permission of the American Academy of Pediatrics from ref. 58.)

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