Role of Pharmacological Modulation of Tonic Inhibition in Hippocampal Sharp Wave Ripples Amplitude and Place Cell Firing Dynamics

Abstract

Hippocampal hyperactivity is a hallmark of memory dysfunction associated with age related mild cognitive impairment (aMCI) and Alzheimer’s disease, leading to the hypothesis that hippocampal trisynaptic circuit hyperactivity impairs memory function. As a test of this hypothesis, we sought to pharmacologically recapitulate hyperactivity in young adults by attenuating tonic inhibition in the hippocampal trisynaptic circuit. We used chronically implanted arrays of 96 electrodes arranged as tetrodes and 32 channel silicon probes to record place cell activity within and across the CA1 subregion of young adult rats either foraging in familiar and novel environments or resting in a familiar environment (without foraging) while awake but immobile for ripple band recordings. We demonstrate that oral administration of the nootropic drug α5IA, a selective negative modulator of tonically active predominantly extrasynaptic α5 GABA receptors, enhances CA1 place cell firing rates but does not augment spatial information content or pattern separation expected a priori to reflect nootropic drug action. This conundrum is resolved by the finding that α5IA substantially increases the sharp wave ripple (SPW‐R) amplitude, which is known to correlate with improved remembering. We replicated to result in three strains of rats (Long Evans, Fisher 344, and Sprague Dawley) and found that the outcomes were not strain specific. These observations indicate that the nootropic actions of α5IA may result from enhancement of aspects of memory function influenced by CA1 SPW‐R amplitude such as consolidation of encoded information. We posit that modulation of ripple dynamics may be controlled via alterations in extrasynaptic tonic inhibition mediated in part by α5 GABA‐A receptors.