HIGHER-ORDER THALAMUS IS PIVOTAL IN SCHIZOPHRENIA-ASSOCIATED PATHOPHYSIOLOGY

Synaptic dysfunction has been proposed as cellular pathophysiology underlying schizophrenia, yet the brain-wide distribution of dysfunctional circuits at single-neuron resolution has remained unknown. Here, we perform comprehensive multi-probe electrophysiological investigations in vivo in the Grin2a^+/- preclinical model for schizophrenia and control animals, recording individual neurons across ~45 brain regions spanning cortex, striatum, hippocampus, and thalamus. Mutants displayed distributed and graded alterations across regions, with prominent activity reductions in higher-order thalamus and cross-parameter alterations across prefrontal cortices, striatum, and hippocampus compared to controls. Restoration of higher-order thalamic activity in mutants was sufficient to normalize alterations in connected prefrontal cortices and striatum and cascaded to hippocampus and sensory cortices. Accordingly, thalamic restoration in mutants normalised aberrant neural responses throughout the brain in response to movement, reward, and unexpected stimuli. Thus, higher-order thalamus plays a pivotal role in schizophrenia-associated pathophysiology and restoration of a single informed locus could present a potent therapeutic strategy.