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P601. Kalrn Mutation Identified in Individuals With Schizophrenia Recapitulates Disease-Relevant Neuro-oscillatory Aberrations in the Mouse Visual and Prefrontal Cortices

      Background

      Aberrations in basic sensory cortical processing are present in several neuropsychiatric disorders. Electrophysiological biomarkers of sensory processing dysfunction can be reliably measured in both human patients and animal models, providing a translational strategy for linking molecular, circuit, and cognitive aspects of the disease. We recently developed a mouse model with a mutation in the Kalrn gene observed in a cohort of individuals with schizophrenia. These Kalrn-PT mice recapitulate structural changes in patients with schizophrenia, including adolescent-onset dendritic changes in the neocortex. Here we sought to understand how these structural changes may affect neural synchrony in local and interregional cortical circuits, focusing on a sensory processing paradigm with established disease relevance.

      Methods

      We recorded dual local field potentials (LFPs) from primary visual cortex (V1) and anterior cingulate area (ACA) in awake mice during a visual oddball sequence, a clinically-relevant sensory stimulation paradigm used to quantify “mismatch negativity.” Adult male and female mice (P84-140) were used; we recorded from homozygous Kalrn-PT mutants (n=7) and their wildtype littermate controls (WT; n=7).

      Results

      In V1, the Kalrn-PT mice exhibited diminished stimulus-induced broadband gamma power (Glass’s Δ = 0.621) and altered context-dependent gamma power responses (Glass’s Δ = 0.634), suggesting a disrupted “mismatch negativity” producing circuitry. Further, interregional phase synchrony between ACa and V1 was decreased in Kalrn-PT mice during the oddball paradigm, particularly in the theta-alpha band.

      Conclusions

      These results suggest that Kalrn-PT mutations likely affect inter-regional circuitry which underlies contextual processing of sensory information, potentially by impacting dendrite-targeted long-range inputs and inhibition via SST+ interneurons.

      Supported By

      NIMH (R00MH115082); Whitehall Foundation; GSU Center for Neuroinflammation and Cardiometabolic Diseases

      Keywords

      Schizophrenia, Mismatch Negativity, Mouse Model, Local Field Potentials, Visual Processing