The brain has likely evolved multiple control mechanisms to regulate activity and keep it in a robust operational state. Occasionally these regulatory mechanisms break down, and uncontrolled activity in the form of epileptic seizures ensues. This is especially evident in the syndrome of primary generalized epilepsy in which global seizures suddenly arise from a normal behavioral state. A form of primary generalized epilepsy, absence epilepsy, is expressed in a network composed of widespread regions of neocortex and a subcortical structure, the thalamus, that together form the thalamocortical circuit. Childhood absence seizures are characterized by widespread synchronized thalamocortical activity, EEG 3/s spike and wave discharge, and loss of consciousness. Validated genetic rat and mouse models of absence epilepsy have identified some of the thalamic and cortical microcircuit elements, i.e. the individual neuron types and their synaptic connections that participate in the epileptic network, yet it remains unclear how the circuit suddenly and unpredictably switches its state from that of normal functioning to seizure generating and back. Recent evidence suggests that in one central node of the thalamocortical network, the reticular thalamus (RT), a single type of branch of RT neuron axonal output is specifically susceptible to sporadic failures that might explain sudden seizure onset. Pilot data indicate that this internal branch, which regulates RT itself, can fail in a use-dependent way that would lead to uncontrolled RT activity that can precipitate seizures. Further, Scn8a deficient mice, with frequent absence seizures, show increased intra-RT failures, indicating a causative role. Only recently have the methods become available to directly study axon function, allowing us for the first time ask questions about how the selective failure of neurotransmission in axon branches can occur. Experiments will utilize high resolution 2 photon imaging and electrophysiology to visualize the different branches of RT axons and address the novel hypothesis that failure, i.e. the inability to send efferent synaptic signals, through individual output axon branches and their synaptic release sites could be causative in epilepsy.
Aims will determine the conditions in which selective branch failure of intra-RT vs RT output axons to the dorsal thalamus occurs, and the mechanisms for the failure, whether they be through failure of action potential generation or through decreased probability of synaptic release, and whether failure mechanisms may apply more broadly to epilepsies. The results of these studies could inform the development of potential new epilepsy treatment approaches that would prevent the failure of key output branches.

Public Health Relevance

Epilepsy is a neurological condition occurring in about 1% of the population, in which sudden, unexpected seizures interrupt thoughts and actions. Epileptic seizures happen when the brain temporarily enters into a state where neural electrical activity becomes uncontrolled. The proposed experiments will test whether seizures may start when a particular communication channel between neurons in the thalamus suddenly breaks down.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1)
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Whittemore, Vicky R
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Stanford University
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