Neuroprotectin D1 Attenuates Epileptogenesis (IN5-1.001)

Abstract

Objective: We determined the role of NPD1 in the development of recurrent seizures in a post status epilepticus model of epileptogenesis. Background Epileptogenesis involves neuroinflammatory signaling that contributes to synaptic activity dysfunction that leads to neuronal network rearrangement and fosters recurrent seizures. Neuroprotectin D1 (NPD1) a derivative of the omega 3 fatty acid, docosahexaenoic acid, limits seizures susceptibility and induces neuroprotection after brain injury. Design/Methods: Multi-microelectrodes were implanted in the dorsal hippocampus in adult male mice after status epilepticus (SE) induced by pilocarpine. NPD1 or Vehicle was administered systemically during the 5 days after SE. Local field potentials and spike units from hippocampal regions were recorded using data acquisition systems at different time points. Time-dependent changes of the oscillatory activity of hippocampal networks were analyzed, including interictal spikes (IS), microseizures, high frequency oscillations, and spike unit activity. Recurrent seizure activity was video-recorded during the 3 weeks after SE. Brains were dissected and dendrites of principal cells from hippocampal regions were analyzed using Golgi staining. Results: Microseizures were observed during epileptogenesis in different hippocampal layers at frequencies of 4-8 microseizures/min. Frequencies above 150 Hz (high-frequency oscillations; HFOs) were observed in all hippocampal fields but were increased only in the dentate gyrus. The interictal period showed burst-like neuronal activity with a prolonged period of inactivity (a sustained firing pattern in control animals) and were correlated with a loss of dendritic spines. NPD1-treated mice had less recurrent seizure frequency and duration. During epileptogenesis, NPD1 attenuates pathological HFO and microseizures, and increases the power of theta activity. Conclusions: We suggest that microseizures are modifications of the existent neuronal network within inter-connected microdomains, and bursting neurons could act as a kindling-like mechanism that synchronizes HFOs with other microdomains. The NPD1 bioactivity in epileptogenesis suggests protection of neuronal circuitry at the post synaptic levels. Supported by: NIH P20RR016816. Disclosure: Dr. Musto has nothing to disclose. Dr. Khoobehi has nothing to disclose. Dr. Walker has nothing to disclose. Dr. Bazan has nothing to disclose.