Sunday, June 1, 2025
6/1/2025
Inhibitory Network Plasticity in Neurological Disease - Project Summary: Temporal lobe epilepsy (TLE) develops in a third of over 300,000 patients and lead to long term memory and cognitive disorders which impact quality of life. The dentate gyrus, a circuit severely impacted in hippocampal sclerosis in TLE, serves as the first node in the flow of cortical information to the hippocampus. The dentate gyrus is a critical for episodic memory function and is proposed to discriminate highly similar inputs through a process known as pattern separation, the underlying mechanisms of which are not fully understood. The dentate receives highly structured inputs with lateral entorhinal cortical projections with content or object related information targeting the distal dendrites of the granule cells through the lateral perforant path and spatial and contextual information from the medial entorhinal cortex reaching the middle dendrites through the medial perforant path. However, the circuit mechanisms underlying how these inputs streams are processed to discriminate subtle differences in each modality, how they are associated to form episodic memory representations and their contribution to dentate electrical activity patterns associated memory consolidation and recall are not known. We propose that input specific recruitment of inhibitory neurons and their layer specific inhibition of granule cell dendrites is critical for the ability of the dentate to decorrelate distinct input streams. Since dendrite targeting dentate interneuron subtypes undergo extensive structural and functional plasticity in epilepsy, we further propose that seizure induced changes in dendritic inhibition compromise input specific recruitment of inhibition and undermine input output transformations. Combining electro- and optophysiology in ex vivo slices from transgenic mice subject to experimental epilepsy and behavioral and multisite recordings with optogenetic interrogation will allow us to address these questions. Aim 1 will develop a fundamental understanding of input specific and recruitment, and frequency dependent dynamics of dentate interneuron subtypes and how it is altered in epilepsy. Aim 2 will determine the role of somatic and dendritic inhibition in dentate decorrelation of layer specific inputs and their transformations in epilepsy at the circuit level. Finally, Aim 3 will examine determine the role of inhibitory neuron subtypes to behavioral spatial and object discrimination and electrical correlates of dentate memory processing in control and epileptic mice. in line with the proprieties established in the 2021 AES/NINDS Epilepsy Research Benchmarks, these studies will address mechanisms underlying neuropsychiatric comorbidities in epilepsy and is of broader relevance to understanding memory processing and decline in ageing and Alzheimer’s Disease.
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