INHIBITING SST CHODL NEURONS RESCUES SLEEP DYSFUNCTION IN A MOUSE MODEL OF SCHIZOPHRENIA

Cognitive impairment is among the most treatment-resistant features of schizophrenia and is tightly linked to disruptions in sleep-wake regulation. Notably, sleep disturbances often precede the first clinical symptoms in patients, suggesting that sleep circuit dysfunction may be an early and fundamental component of disease progression. However, the specific neuronal substrates connecting early sleep dysregulation to later cognitive decline remain poorly understood.
Using the human-relevant 15q13.3^+/− microdeletion mouse model of schizophrenia, we generated a single-nucleus transcriptomic dataset of over 120,000 cortical nuclei and combined this with Patch-seq, ex vivo calcium imaging, and detailed sleep phenotyping across REM, NREM, and wake states. This multimodal approach revealed a maturation-dependent vulnerability in a rare population of long-range cortical GABAergic interneurons: Sst-Chodl cells. While these neurons are transcriptionally and functionally indistinguishable from controls during juvenile stages, they become selectively hyperactive in adulthood, in contrast to the global hypoactivity observed across other Sst subtypes.
This cell-type-specific divergence coincides with the emergence of sleep-wake fragmentation. Targeted chemogenetic inhibition of Sst-Chodl neurons using DREADDs was sufficient to rescue the sleep phenotype, demonstrating a causal role for this population in sleep circuit dysregulation.
Together, these findings identify Sst-Chodl neurons as a previously unrecognised circuit node linking genetic risk, early sleep disruption, and cognitive impairment in schizophrenia, and suggest a precise cellular target for therapeutic strategies beyond conventional antipsychotics.