Abstracts

Rationale: Excessive excitatory or altered inhibitory signaling is proposed to underlie the abnormal synchrony of hippocampal neuronal networks which are thought to contribute to seizures in human and experimental temporal lobe epilepsy (TLE). Increased dentate granule cell (DGC) neurogenesis is implicated in these epileptogenic mechanisms, as DGCs born around or shortly after the time of epileptogenic insult, especially hilar-ectopic DGCs, show abnormal integration into pre-existing circuits. However, specific alterations in both glutamatergic and GABAergic innervation of individual, birthdated DGCs during epileptogenesis has not been studied before. Methods: studied before. We investigated changes in excitatory and inhibitory synaptic inputs onto individual DGCs born during epileptogenesis using retroviral DGC labelling and whole cell voltage clamp techniques in the rat pilocarpine model of TLE. We compared neurons born shortly after induction of status epilepticus (SE) in adult male rats with DGCs born neonatally in age-matched controls after SHAM treatment. Additionally, ongoing studies are investigating synaptic balance in adult-born DGCs from SHAM animals. Birthdating of DGCs was achieved using retrovirus expressing GFP or mCherry driven by a synapsin promoter. All electrophysiological recordings were performed 8 to 10 weeks after SE or SHAM. Results: We recorded both glutamatergic and GABAergic spontaneous synaptic activity in normal mature DGCs and those born during epileptogenesis. We calculated ratios of frequencies and amplitudes of excitatory to inhibitory postsynaptic currents (PSCs) to compare the synaptic balance index for individual neurons. This allowed us to identify candidate hub neurons exhibiting a disproportionately high contribution of one type of synaptic inputs over another. The vast majority of adult-born DGCs in the epileptic brain did not differ from normal controls; however, a small fraction, approximately one in 15 cells, showed a substantial increase in the ratio of glumatergic to GABAergic PSCs frequencies. Conclusions: We speculate that those cells serve as network hubs facilitating seizure development after an epileptogenic insult. An understanding of DGC integration into pre-existing networks may be crucial for the development of antiepileptogenic therapies. Funding: 2017 AES Postdoctoral Fellowship NIH NS 058585