Hyperexcitability and Hypersynchrony Hallmarks of Epileptic Neurons

How is normal neuronal firing altered in epilepsy? The pathophysiology of epilepsy has two distinct but related hallmarks: hyperexcitability and hypersynchrony (33,34). Hyperexcitability is the abnormal responsiveness of a neuron to an excitatory input; the neuron tends to fire multiple discharges instead of the usual one or two. Hypersyn-

Table 3

Roles of Channels and Receptors in Normal and Epileptic Firing

Channel or receptor Voltage-gated Na+ channel

Voltage-gated K+ channel

Ca2+-dependent K+ channel

Voltage-gated Ca2+ channel

Non-NMDA receptor

NMDA receptor

GABAa receptor GABAB receptor Electrical synapses

Na-K pump

Role in normal neuronal function

Subthreshold EPSP; action potential upstroke Action potential downstroke

AHP following action potential;

sets refractory period Transmitter release; carries depolarizing charge from dendrites to soma Fast EPSP

Prolonged, slow EPSP

IPSP

Prolonged IPSP Ultrafast excitatory transmission Restores ionic balance

Possible role in epilepsy

Repetitive action potential firing

Abnormal action potential repolarization Limits repetitive firing

Excess transmitter release; activates pathologic intracellular processes Initiates paroxysmal depolarization shift (PDS) Maintains PDS; Ca2+ activates pathological intracellular processes Limits excitation Limits excitation Synchronization of neuronal firing Prevents K+-induced depolarization chrony refers to the recruitment of large numbers of neighboring neurons into an abnormal firing pattern. Ultimately, epilepsy is a network phenomenon requiring participation of many neurons firing synchronously. What happens in the normally functioning brain to cause it to fire hypersynchronously, and what are possible mechanisms for excitation to increase, inhibition to diminish, or both?

Figure 5 provides a schematic overview of normal, interictal (between seizures), and ictal (during a seizure) physiological events at the level of the whole brain and in a simplified neuronal circuit. First, consider the widespread cortical networks in the top panel. Normally, excitation and inhibition in neocortex are relatively balanced. Neurons are activated when needed; otherwise they are quiescent. The EEG in the normal situation (left column) shows low-voltage "desynchronized" activity—that is, neurons in the region under the electrode are not firing synchronously. If a large number of neurons, perhaps thousands or more, begin to fire synchronously in an area of cortex, a so-called EEG spike or interictal discharge is recorded on the EEG (middle column). The larger the area of cortex involved, the greater the spread of such an interictal discharge. In Fig. 5, the largest concentration of neurons firing synchronously is under electrode 2, though electrode 1 also detects some spread of the abnormal firing, recorded as a small discharge or "sharp wave." Interictal spikes are typically 30-50 ms in duration. The third column depicts the ictal state (seizure), with a barrage of rapidly firing EEG spikes in electrodes 2 (with spread to electrode 1), which may continue for many seconds or minutes. At this point, a

Fig. 5. Abnormal neuronal firing at the levels of (A) the brain and (B) a simplified neuronal network consisting of two excitatory neurons, 1 and 2, and an inhibitory interneuron, 3. EEG (top set of traces) and intracellular recordings (bottom set of traces) are shown for the normal (left column), interictal (middle column), and ictal conditions (right column). Numbered traces refer to like-numbered recording sites. Note time-scale differences in different traces. (A) Three EEG electrodes record activity from superficial neocortical neurons. In the normal case, activity is low voltage and "desynchronized" (neurons are not firing together in synchrony). In the interictal condition, large "spikes" are seen focally at electrode 2 (and to a lesser extent at electrode 1, where they are termed "sharp waves"), representing synchronized firing of a large population of hyperexcitable neurons (expanded in time in B). The ictal state is characterized by a long run of spikes. (B) At the neuronal network level, the intracellular correlate of the interictal EEG spike is called the paroxysmal depolarization shift (PDS). The PDS is initiated by a non-NMDA-mediated fast EPSP (shading) but is maintained by a longer, larger NMDA-mediated EPSP. The post-PDS hyperpolarization (asterisk) temporarily stabilizes the neuron; if this post-PDS hyperpolarization fails to restore membrane potential to the resting level (right column, thick arrow), ictal discharge can occur. The lowermost traces, recordings from neuron 2, show activity similar to that recorded in neuron 1, occurring a bit later owing to a synaptic delay (double-headed horizontal arrow). Activation of inhibitory neuron 3 by firing of neuron 1 prevents neuron 2 from generating an action potential (the IPSP counters the depolarization caused by the EPSP). But if neuron 2 does reach firing threshold, additional neurons will be recruited, leading to an entire network firing in synchrony (seizure!). (Modified with permission of the American Academy of Pediatrics from ref. 58.)

Fig. 5. Abnormal neuronal firing at the levels of (A) the brain and (B) a simplified neuronal network consisting of two excitatory neurons, 1 and 2, and an inhibitory interneuron, 3. EEG (top set of traces) and intracellular recordings (bottom set of traces) are shown for the normal (left column), interictal (middle column), and ictal conditions (right column). Numbered traces refer to like-numbered recording sites. Note time-scale differences in different traces. (A) Three EEG electrodes record activity from superficial neocortical neurons. In the normal case, activity is low voltage and "desynchronized" (neurons are not firing together in synchrony). In the interictal condition, large "spikes" are seen focally at electrode 2 (and to a lesser extent at electrode 1, where they are termed "sharp waves"), representing synchronized firing of a large population of hyperexcitable neurons (expanded in time in B). The ictal state is characterized by a long run of spikes. (B) At the neuronal network level, the intracellular correlate of the interictal EEG spike is called the paroxysmal depolarization shift (PDS). The PDS is initiated by a non-NMDA-mediated fast EPSP (shading) but is maintained by a longer, larger NMDA-mediated EPSP. The post-PDS hyperpolarization (asterisk) temporarily stabilizes the neuron; if this post-PDS hyperpolarization fails to restore membrane potential to the resting level (right column, thick arrow), ictal discharge can occur. The lowermost traces, recordings from neuron 2, show activity similar to that recorded in neuron 1, occurring a bit later owing to a synaptic delay (double-headed horizontal arrow). Activation of inhibitory neuron 3 by firing of neuron 1 prevents neuron 2 from generating an action potential (the IPSP counters the depolarization caused by the EPSP). But if neuron 2 does reach firing threshold, additional neurons will be recruited, leading to an entire network firing in synchrony (seizure!). (Modified with permission of the American Academy of Pediatrics from ref. 58.)

huge number of neurons is firing synchronously, the result of which would be a clinical seizure with manifestations correlating with the area of brain involved.

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