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P557. Mutations in Kalrn Disrupt Gamma-Band Oscillations in the Auditory Cortex of Adult Mice

      Background

      Neuropsychiatric disorders such as schizophrenia exhibit disordered sensory cortical function. Dendritic and synaptic impairments may form the basis of such dysfunction. The KALRN gene codes for multiple isoforms that serve various roles in regulating dendritic and synaptic biology. Modeling a naturally occurring mutation in Kalrn (Kalrn-PT mouse model) that affects the longer, dual active domain isoforms, recapitulated an adolescent-onset reduction in dendritic length and complexity in Layer 3 pyramidal neurons in the primary auditory cortex (A1). We sought to understand how such neuronal morphology and anatomy changes may relate to disordered sensory cortical function.

      Methods

      We employed the steady-state auditory response (aSSR) paradigm to quantify cortical neurooscillatory deficits in schizophrenia. We recorded bipolar local field potentials (LFPs) implanted ≈300 μm deep in A1 in awake mice, presenting a 1-second pure-tone auditory stimulus (70 dB), from 2kHz to 21kHz, sinusoidally modulated at 40-Hz (gamma-band). Baseline and stimulus-induced power and phase-locking at 40-Hz were quantified in the LFP. Adult male and female mice (P84-154) were homo-(n=6) or heterozygous (n=6) Kalrn-PT mutants and littermate wild-type controls (WT; n=8).

      Results

      In A1, mutants displayed increased background power (i.e., noise) across all frequencies. Interestingly, 40-Hz aSSRs were not altered in Kalrn-PT mutants, yet induced (non-phase-locked) gamma power was reduced in mutants.

      Conclusions

      Stimulus-locked aSSR entrainment, reflecting feed-forward thalamocortical drive and PV-interneuron-based inhibition, was not affected. Still, non-stimulus-locked gamma-band activity (reflecting local or feedback inputs, mediated by SST-positive interneurons) was reduced. This is consistent with known deficits in dendrites in Kalrn-PT mutants in layer 3 of the auditory cortex.

      Supported By

      NIHMH, Whitehall Foundation, CNCD Fellowship

      Keywords

      Gamma Oscillation, EEG, Schizophrenia