Normal Synaptic Function And Neuronal Firing

As a preface to consideration of the abnormal firing seen in epilepsy, a review of normal synaptic transmission and neuronal firing is required. Neurons generally are one of two basic types, excitatory or inhibitory, depending on the neurotransmitter released from the neuron's terminals (Fig. 2). When a neuron is activated, it releases a transmitter from prepackaged vesicles in presynaptic terminals, a process that requires presy-

A Inhibitory

Presynaptic Postsynaptic

B Excitatory

NMDA receptor-ion pore complex

glutamate binding site ^

site u ion pore

Fig. 2. Normal synaptic transmission showing representative inhibitory and excitatory presynaptic terminals and postsynaptic neurons. (A) Inhibitory synapse. GABA (solid circles) binding to its postsynaptic GABAa receptors allows influx of Cl- ions, hyperpolarizing the postsynaptic neuron (IPSP; see text). GABA is synthesized from glutamate in a reaction catalyzed by glutamic acid decarboxy-lase (GAD), using pyridoxine (vitamin B6) as a cofactor. (B) Excitatory synapse. Glutamate (open circles) released from the terminal crosses synaptic cleft and binds to one of several glutamate receptor subtypes (NMDA or non-NMDA; see text). Binding to non-NMDA receptors causes a fast EPSP; binding to NMDA receptors produces a longer, slow EPSP. If the postsynaptic neuron is sufficiently depolarized to reach firing threshold, an action potential will occur. Inset (box) shows details of the NMDA receptor-ion pore complex. For the NMDA ion pore to open, several events must occur: glutamate (open circle) must bind to the receptor, glycine (triangle) must bind to its own receptor site on the NMDA receptor complex, and when the cell is sufficiently depolarized, Mg2+ must leave the channel pore. Only then can Na+ and Ca2+ flow into the neuron and produce a prolonged NMDA-mediated EPSP. (Modified with permission of the American Academy of Pediatrics from ref. 58.)

naptic calcium influx. Vesicle fusion with the presynaptic terminal membrane allows release of the neurotransmitter, which then diffuses across the synaptic cleft and binds to its specific receptor on the postsynaptic membrane. Binding of a neurotransmitter to its receptor activates a cascade of events, involving ion fluxes through the receptor and a subsequent change in excitability of the postsynaptic cell (depolarization or hyperpolar-ization—that is, movement of the membrane potential closer to or further away from the threshold voltage for action potential generation, respectively). Since some neuro-transmitters (ligands) causes the opening of ion channels, they are referred to as ligand-gated channels. Alternatively, ion channels may opened by voltage (voltage-gated channels), as discussed later.

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