Changes in nonlinear signal processing in rat hippocampus associated with loss of paired-pulse inhibition or epileptogenesis

Abstract

Purpose: To study acute and chronic physiological effects of perforant path stimulation using paired-pulse and nonlinear signal analysis techniques (Wiener kernel analysis). Methods: Two to 3-month-old Wistar rats were implanted with stimulating electrodes in the perforant path and recording electrodes in the granule cell layer. Loss of paired-pulse inhibition was produced with 2 Hz continuous and 20 Hz (10 s/min) intermittent stimulation for periods of 1-15 min (0.1 ms, 20 v pulses). Some animals received 30-60 min of stimulation, a model for status epilepticus/epileptogenesis. Responses to paired-pulse or white noise inputs were recorded sequentially. Results: Loss of inhibition with brief 1-3 min of stimulation, measured by increase paired-pulse ratio (P2/P1 ISI 40 ms) from 0.25 (±0.27) pre- to 1.02 (±0.18) poststimulation (p < 0.001), lasted 43 (±15) min. For 30-60 min of stimulation, the paired-pulse ratios were 0.088 (±0.11), 1.59 (±0.036), 0.06 (±0.11), 0.82 (±0.22) for pre-, immediate post-, 1 week post-, and 1 month poststimulation, respectively (p < 0.025). Compared to prestimulation values, Wiener kernel amplitudes for immediate, 1 week, and 1 month poststimulation were 24% (±13%), 72% (±17%), and 31% (±21%), respectively (p < 0.05). Wiener kernels 1 month poststimulation showed response prolongation with increased opportunity for excitatory interactions of inputs (particularly those separated by 4 ms). Conclusions: Brief perforant path stimulation causes sustained loss of inhibition in the dentate, possibly an early event in the transition to status epilepticus. Stimulation for 30-60 min causes chronic changes in paired-pulse and white noise (Wiener kernel) responses. Transient recovery occurs by 1 week, but later new features appear (including delayed/late inhibition and potential excitatory cross-talk) that might favor epileptic seizures.