The Role of Dentate Spikes in Cognition and Epilepsy

/Abstract Temporal lobe epilepsy (TLE) is a debilitating disorder that includes pervasive memory impairments that significantly impact quality of life, yet have no available treatment options. In both patients and rodent models of TLE, altered neural circuits lead to both hypersynchronous events like seizures, interictal epileptiform discharges (IEDs), and high frequency oscillations (HFOs), as well as desynchronization, with reduced coherence of oscillations and neural phase locking across regions. These changes in synchronization within and across brain regions are likely to disrupt normal cognitive function and contribute to memory impairment. One important mechanism of synchronization in the healthy brain is the dentate spike, a large-amplitude event that can occur along with synchronous neural activity across the brain. Yet, little is known about how these events are initiated, how they drive synchronous neural activity, and how they contribute to spatial memory. In Aim 1 of this proposal, we will use in vivo electrophysiology with silicon probes to characterize how neural activity is synchronized across medial entorhinal cortex (MEC) and hippocampus during type 2 dentate spikes (DS2s), which are hypothesized to be driven by inputs from layer 2 stellate cells in MEC. We will optogenetically identify these MEC2 stellate cells and both stimulate and inhibit them to determine their causal role in DS2 generation and neural synchronization. Then, in Aim 2, we will examine how DS2 rates and neural synchronization are altered in the pilocarpine-induced status epilepticus mouse model of TLE. In addition, we will record and directly manipulate MEC2 stellate cells during a cognitive task to determine their causal role in spatial cognition, and how they mediate memory impairment in epilepsy. Together, these Aims will determine the precise neural circuits that drive DS2 events and associated neural synchronization, and test how these events and synchronization processes are disrupted in chronically epileptic mice. Project Number: 1R01NS145154-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Tristan Shuman | Institution: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY | Award Amount: $667,738 | Activity Code: R01 | Study Section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT] View on NIH RePORTER: https://reporter.nih.gov/project-details/11367726