Altered thalamo–prefrontal synchrony dynamics during spatial working memory task performance in a SETD1A loss-of-function mouse model of schizophrenia predisposition

ABSTRACT Schizophrenia is associated with profound working memory deficits, for which there are no approved treatments. Rare heterozygous null mutations in SETD1A , a gene encoding a key epigenetic regulatory protein, have been definitively linked to increased risk for schizophrenia and neurodevelopmental disorders. To investigate how SETD1A haploinsufficiency impacts the function of circuits supporting working memory, this study examined neural oscillatory synchrony across a network of brain regions critical for spatial working memory (SWM) in mice carrying a loss-of-function allele in the orthologous SETD1A gene. Local field potential recordings were performed in the prefrontal cortex, dorsal and ventral hippocampus, and thalamic nucleus reuniens in male and female wildtype and Setd1a +/– mice performing a delayed non-match to sample task of SWM. Setd1a +/– mice exhibited unaltered prefrontal-hippocampal neural oscillatory synchrony across frequencies and task epochs. In contrast, Setd1a +/– mice displayed reduced beta-frequency synchrony between the prefrontal cortex and nucleus reuniens during SWM maintenance and blunted bidirectional modulation of prefrontal-reuniens beta- and gamma-frequency synchrony across SWM task epochs. Collectively, this work expands our understanding of how genetic risk for schizophrenia alters functional connectivity within distributed circuits supporting SWM. GRAPHICAL ABSTRACT