Abstracts

Rationale: CNS infections are a major risk factor for the development of temporal lobe epilepsy, a form of epilepsy that is often drug resistant and not well understood. In the Theiler's virus mouse model of infection-induced epilepsy, mice exhibit acute post-infection seizures and develop spontaneous seizures by 2 months after infection. Recent work from our laboratory has shown that the hippocampal CA3 excitatory circuit exhibits different characteristics during the acute infection period versus chronic time points. The current study tests the hypothesis that inhibition is also altered and effects network activity in the CA3 region of the hippocampus as a consequence of infection and during epileptogenesis. Methods: Mice were intracerebrally injected with either PBS or Theiler's virus (2 - 3.5 x 107 PFU) and were sacrificed on days 3-7 post-injection for the acute period or left to recover for at least 2 months before sacrifice. Hippocampal slices including CA3 were cut in ice-cold sucrose. CA3 hippocampal neurons were patch clamped in Ringer's solution containing CNQX (10 μM) and APV (100 μM) for recording IPSCs. After baseline activity of sIPSCs was established, TTX (1 μM), was washed on for 15 min to record mIPSCs. Amplitude and frequency of both sIPSCs and mIPSCs were measured. Field potentials in CA3 were evoked via stimulation of afferents for 30 minutes (0.03 Hz) in normal ACSF and for 30 minutes following blockade of inhibition with picrotoxin (100 μM). Results: All TMEV infected mice used in the study were observed to have seizures during the acute infection period. In brains slices prepared during the acute infection period, recordings of sIPSCs revealed a significant decrease in frequency (p=.015) and amplitude (p=.019). In addition, there was a significant decrease of the mIPSC amplitudes (p=.015). Surprisingly, no decreases in either frequency or amplitude were observed in sIPSCs or mIPSCs in brain slices prepared at the 2 month time point. Field potentials elicited in CA3 by stimulation of afferent input were significantly smaller in TMEV-infected mice relative to controls at both time points as measured by coastline burst analysis. Additionally, the coastline burst index (CBI) following blockade of inhibition was unchanged during the acute period. However, the CBI was unexpectedly smaller at the chronic time point (p=.035) in TMEV-infected mice. Conclusions: The CA3 inhibitory network is differentially altered by TMEV infection during the acute infection period relative to the chronic epilepsy time point as evidenced by sIPSCs and mIPSCs. While there was an initial reduction of inhibition during the acute infection period, there was an apparent recovery of inhibition at later time points. However, the reduction of field potentials following infection at both time points and the decreased CBI following blockade of inhibition at the chronic time point suggest a complicated network phenomenon.[Supported by NINDS grants R01NS065434 (KSW & HSW) and 1R01NS065714 (RSF), CURE, Margolis Foundation, and Robert and Joyce Rice]