Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models.

Neuropsychiatric disorders are often accompanied by cognitive impairments/intellectual disability (ID). It is not clear whether there are converging mechanisms underlying these debilitating impairments. We found that many autism and schizophrenia risk genes are expressed in the anterodorsal subdivision (AD) of anterior thalamic nuclei, which has reciprocal connectivity with learning and memory structures. CRISPR-Cas9 knockdown of multiple risk genes selectively in AD thalamus led to memory deficits. While the AD is necessary for contextual memory encoding, the neighboring anteroventral subdivision (AV) regulates memory specificity. These distinct functions of AD and AV are mediated through their projections to retrosplenial cortex, using differential mechanisms. Furthermore, knockdown of autism and schizophrenia risk genes PTCHD1 , YWHAG , or HERC1 from AD led to neuronal hyperexcitability, and normalization of hyperexcitability rescued memory deficits in these models. This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models. [Display omitted] • AD thalamus is necessary for memory encoding • AV thalamus regulates memory specificity • Knockdown of autism and schizophrenia risk genes from AD leads to cognitive deficits • Disease models exhibit converging cellular and circuit mechanisms in AD Neuropsychiatric disorders are often accompanied by cognitive impairments. Roy et al. report that the knockdown of several autism and schizophrenia risk genes from anterodorsal thalamus leads to hyperexcitability and cognitive deficits. Normalization of hyperexcitability rescues cognitive deficits across models, revealing a converging mechanism underlying cognitive deficits. [ABSTRACT FROM AUTHOR]