Seizure-Induced Remodeling of Cholinergic Networks in Dravet Syndrome

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

ABSTRACT Epilepsy is characterized by recurrent seizures, but its associated comorbidities – including attention deficits, mood disorders, cognitive impairment, and sleep disorders – are prevalent and often highly detrimental to quality of life. Current treatments do not specifically prevent or reverse these epilepsy-associated comorbidities, and progress in developing targeted therapies has been hampered by an incomplete mechanistic understanding of how seizures remodel relevant networks. Cholinergic neurons, located in discrete nuclei within the brainstem and basal forebrain, play critical roles in regulating attention, mood, cognition, and sleep through widespread projections across the central nervous system. Case reports and preliminary data suggest altered cholinergic function in epilepsy, but a comprehensive understanding of these changes remains lacking. This proposal aims to mechanistically link acute seizures with chronic alterations in cholinergic networks, thereby identifying targets for next-generation therapeutics. Specifically, our primary objective is to delineate seizure-associated pathology in the cholinergic pedunculopontine nucleus (PPN) utilizing a mouse model (Scn1a+/-) of Dravet Syndrome, a severe developmental and epileptic encephalopathy. Our central hypothesis is that overactivation of cholinergic neurons by seizures chronically alters ascending cholinergic network function due to a downregulation of acetylcholine expression. In Aim 1, we will establish the causal role of neuronal activity in cholinergic neuron loss. We will test whether seizure-induced hyperactivation is necessary and sufficient to reduce cholinergic neuron numbers in the PPN by inhibiting these neurons during seizures in Scn1a+/- mice and activating them exogenously in wild-type mice. In Aim 2, we will identify seizure-induced functional changes in cholinergic PPN circuitry by quantifying downstream cholinergic neurotransmission and sleep architecture integrity. We will test these measures of PPN circuit functionality both across genotypes (Scn1a+/- versus wild-type littermate control mice) and within animals (before versus after repeated seizure induction). In Aim 3, we will test whether the observed decrease in cholinergic neuron number in Scn1a+/- mice results from an activity-dependent phenotypic switch from cholinergic to GABAergic expression. The results from these aims are expected to demonstrate that seizures induce an activity-dependent reduction in cholinergic neurons, impair cholinergic network activity, and alter neurotransmitter expression patterns in Scn1a+/- mice. These findings will identify vulnerable neuronal populations and circuits as targets for therapeutic intervention, potentially leading to novel strategies to protect against debilitating comorbidities in patients with epilepsy.