Excitatory Neurotransmission and Action Potentials 321 Excitatory Chemical Neurotransmission

Excitatory neurotransmission in the brain is mediated largely by the excitatory amino acid, glutamate (Fig. 2B). Glutamate released from presynaptic terminals may bind to any of several glutamate receptor subtypes; for simplicity here, these are denoted as NMDA (N-methyl-D-aspartate) and non-NMDA (kainate and amino-3-hydroxy-5-methyl-isoxasole propionic acid [AMPA]). This confusing nomenclature arose because, experimentally, NMDA is a very selective agonist for one main subtype of glutamate receptor (therefore termed NMDA receptors), whereas AMPA and kainate prefer another type of glutamate receptor (therefore named non-NMDA receptors). However, in real life, glutamate (not NMDA, AMPA, or kainate) is the naturally occurring neurotransmitter; it is a flexible molecule that can bind to both NMDA and non-NMDA receptors, with different physiological consequences in each case. These receptor subtypes must be discussed because of their pivotal importance in the generation and maintenance of epileptic firing.

Non-NMDA receptors mediate the "fast" excitatory neurotransmission ordinarily associated with an excitatory postsynaptic potential (EPSP) (Fig. 3). Binding of glutamate to non-NMDA receptors causes influx of sodium ions (Na+) through the receptor's pore, producing a "fast EPSP" (duration approx 5 ms), followed by an action potential if threshold is reached.

On the other hand, glutamate binding to NMDA receptors sets into motion a somewhat different set of physiological events. For activation of the NMDA receptor, the following must occur: (1) glutamate must bind to the NMDA receptor; (2) glycine, an essential coagonist, must bind at another, nearby site on the NMDA receptor complex; and (3) magnesium ion (Mg2+) block of the channel pore must be removed (Fig. 2B, inset). Mg2+ ions play a unique role in the operation of the NMDA receptor. At resting potential, a Mg2+ ion sits in the pore, preventing influx of any other ions. Once the membrane potential is depolarized by 10-20 mV (by a non-NMDA-mediated fast EPSP), the Mg2+ is expelled from the pore into the extracellular space, allowing Na+ and Ca2+ to flow into the neuron. This gives rise to a prolonged, NMDA-mediated EPSP. Much of the importance of NMDA receptors lies in their ability to allow Ca2+ influx; once inside a neuron, Ca2+ can participate in multiple crucial second-messenger pathways. In the normal brain, NMDA receptors play important roles in learning, in memory, and in the neuronal plasticity that underlies many critical developmental processes. However, if NMDA receptors are overstimulated, the entry of excess Ca2+ can wreak havoc, activating destructive intracellular enzymes, e.g., endonucleases, proteases, which may even lead to cell death. The role of NMDA receptors in epileptic firing is described in Section 4.2.

Non-NMDA and NMDA glutamate receptors are referred to as "ionotropic" or ion permeable. They mediate fast and slow excitatory neurotransmission, respectively. An even slower form of glutamate-mediated excitatory neurotransmission is mediated by another receptor class: metabotropic. Metabotropic receptors operate by means of receptor-activated signal transduction involving membrane-associated G proteins. A variety of metabotropic receptors exist and may regulate neurotransmission at a very fine level. Their importance in epilepsy is just beginning to be appreciated (15).

The depolarization caused by either the fast or slow EPSP also activates voltage-gated ionic channels, such as Na+ or Ca2+, in the membrane; these channels, which

Fig. 4. Electrical synapse. Direct electrical communication via gap junctions allows rapid synchronization of electrical activity between neurons and may play a role in epileptic firing. Neurons 1 and 2 are connected via a gap junction, which allows direct passage of ionic current as well as dye (shading) between cells, when injected intracellularly into cell 1. Cell 3, which has no gap junctions, does not accumulate the dye. When an intracellular current pulse (thin arrow) is injected into cell 1, it is recorded simultaneously in cell 2. When a stronger pulse (thick arrow) is applied, an epileptic burst occurs instantaneously in cells 1 and 2. Electrical synapses provide a means for rapid synchronization of an epileptic circuit.

Fig. 4. Electrical synapse. Direct electrical communication via gap junctions allows rapid synchronization of electrical activity between neurons and may play a role in epileptic firing. Neurons 1 and 2 are connected via a gap junction, which allows direct passage of ionic current as well as dye (shading) between cells, when injected intracellularly into cell 1. Cell 3, which has no gap junctions, does not accumulate the dye. When an intracellular current pulse (thin arrow) is injected into cell 1, it is recorded simultaneously in cell 2. When a stronger pulse (thick arrow) is applied, an epileptic burst occurs instantaneously in cells 1 and 2. Electrical synapses provide a means for rapid synchronization of an epileptic circuit.

are distinct from those opened directly by transmitter binding, become activated and open only at certain membrane potentials. If the sum of depolarizations caused by glutamate receptor activation and by voltage-gated channels is sufficient, firing threshold may be reached, and an action potential will occur. During the longer NMDA-evoked depolarization, several action potentials may fire. Below threshold, EPSPs and IPSPs are engaged in a dynamic, electrical "tug of war," each affecting the membrane potential in the opposite direction. The final membrane potential is the sum of all excitatory and inhibitory inputs, which varies according to the magnitude and timing of each input.

3.2.2. Excitatory Electrical Neurotransmission

In addition to intercellular communication via chemical synapses (excitatory or inhibitory), neurons may interact through electrical (or "electrotonic") synapses (Fig. 4). In contrast to the usual mode of chemical transmission, electrical synapses are specialized sites called gap junctions, closely apposed membranes between two cells through which electrical ionic currents can flow directly. This mode of neurotransmission, which is uniformly excitatory, does not involve the time delay that occurs at a chemical synapse; excitatory current flows directly and immediately from one neuron to its neighbor, with an action potential or even burst of action potentials occurring nearly instantaneously in the two neurons (Fig. 4). The existence of electrotonic transmission was shown in two ways: by direct cell-to-cell transmission when chemical synaptic transmission is blocked (in an environment devoid of Ca2+) and by the passage of a membrane-impermeable dye from one cell to the other.

Electrotonic transmission, though rare by comparison to chemical transmission, has been identified in several parts of the brain. Obviously, if electrotonic transmission were too widespread, unbridled excitation could course through a neuronal network, leading to seizure activity (16,17). In fact, it is thought that electrical synapses mediate some aspects of epileptic synchronization, especially in the developing brain (18). The role of electrical synaptic transmission in epileptogenesis is being explored (17).

3.2.3. Intrinsic Membrane Properties

Synaptic transmission, either by chemical or electrical synapses, allows neurons to communicate with each other. A neuron's excitability (responsiveness to voltage changes) is also determined by its "intrinsic membrane properties," including membrane resistance, subthreshold voltage-dependent ionic channels, and the shape, pattern, and extent of its dendrites and other neuritic processes (collectively known as the neuron's "cable properties") (19). Some cells in the brain possess membrane properties that endow them with a "natural" hyperexcitability. For example, hippocampal CA3 neurons fire in bursts of action potentials under ordinary conditions. Therefore, these neurons may be uniquely qualified to participate in seizure generation and propagation. Intrinsic membrane properties combine with the network's synaptic characteristics to determine ultimate excitability.

3.2.4. Action Potentials

Action potentials are "all-or-none" events; once threshold has been reached, an action potential will fire. The upstroke of the action potential is caused by a huge influx of Na+ through voltage-gated channels, whereas the downstroke is due to efflux of K+ out of the cell through voltage-gated K+ channels. In one recently described epilepsy syndrome, benign familial neonatal convulsions, mutations of voltage-dependent K+ channels were found; such mutations would prolong action potentials by reducing their repolarization rate, thus keeping the neuron depolarized longer and favoring excessive excitation (20).

At the tail end of the action potential, the membrane potential is briefly hyperpolar-ized beyond its original resting level; this is called the afterhyperpolarization (AHP) (Fig. 3). The AHP is mediated by another type of K+ channel, different from the one responsible for the action potential downstroke just discussed and not dependent on voltage but rather on the intracellular Ca2+ level. These "Ca2+-dependent K+ channels" regulate the timing of neuronal firing by governing the neuron's refractory period, the time during which the cell is still recovering from the preceding action potential and cannot yet generate another one. Therefore, these channels can limit repetitive firing and, if they become dysfunctional, epileptic discharges may result.

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