R01NS121106

Control of Axon Initial Segment in Epilepsy - Temporal Lobe Epilepsy (TLE) is the most common epilepsy in adults, and it is frequently refractory to current anti-epileptic drugs, with treatments often exerting a variety of debilitating side effects.

A major barrier for the development of novel treatment strategies is our insufficient understanding of the precise cellular and circuit mechanisms underlying TLE. A centrally important but unresolved question in TLE concerns the mechanisms underlying the excessive, dysregulated production of action potentials at the axon initial segment (AIS) of excitatory principal cells (PCs).

Synaptic control of AIS is provided by a unique, evolutionarily conserved, GABAergic cell-type, the axo-axonic cells (AACs). AACs form synaptic contacts exclusively with the AIS of PCs, placing AACs in a strategic position to control action potential generation. However, due to technical limitations, our knowledge about the in vivo function and regulation of AACs in the normal and epileptic hippocampus has been extremely limited.

Here we propose to employ a combination of recent technical breakthroughs to test hypotheses about the in vivo functional effects, activity dynamics, and efficacy of AAC-mediated control of AIS in mouse models of chronic TLE. The planned project will also determine if it is possible to mitigate epilepsy-related pathologically hyperactive circuits and cognitive deficits through interventions selectively directed at the AAC-dependent, endogenous GABAergic processes regulating AIS in chronic epilepsy.

The proposed project aims to fill a major knowledge gap and address long-standing controversies concerning the interneuronal regulation of AIS in epilepsy by leveraging expertise in novel large-scale, high-resolution in vivo functional imaging techniques in combination with advanced electrophysiological, behavioral, optogenetic, and computational modeling techniques in the CA1 region of the mouse hippocampus.

It is anticipated that defining the function, regulation, and therapeutic potential of AACs in TLE will have a significant impact by advancing our understanding of key circuit control mechanisms in chronic epilepsy and aid the future development of novel anti-epileptic treatment strategies.

The Leland Stanford Junior University

NOT APPLICABLE

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Stanford, California 94305 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 402% from $673,584 to $3,380,533.