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 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. Restoration of higher-order thalamic activity in mutants was sufficient to normalize alterations in connected prefrontal cortices and striatum and unexpectedly cascaded to hippocampus and sensory cortices. Thus, higher-order thalamus plays a pivotal role in schizophrenia pathophysiology and restoration of a single informed locus could present a potent therapeutic strategy.