Early postnatal dysfunction of ACC PV interneurons in Shank3Bmice.

Scientists studied brain development in mice with a genetic change linked to autism (Shank3 deletion). They found that certain brain cells responsible for controlling brain activity became less active very early in development, even though they were receiving normal input signals. These early changes led to problems with brain circuits that help control thinking and social behavior. The research suggests that problems with specific brain cells and channels occur before other autism-related brain changes appear.

This preclinical study investigated brain development in Shank3B mice, an established autism model, focusing on the anterior cingulate cortex (ACC). Researchers found that parvalbumin-expressing interneurons (PVINs) showed reduced activity and excitability as early as postnatal day 15, despite receiving normal glutamate input. These early changes were associated with decreased feedforward inhibition and reduced HCN channel currents. Pyramidal neurons initially appeared normal but also showed HCN channel dysfunction.

By adulthood, both cell types exhibited altered glutamate input and divergent excitability changes. The findings reveal a developmental sequence where PVIN dysfunction precedes broader circuit reorganization, identifying HCN channel problems and impaired inhibition as early pathogenic features.

The identification of early PVIN dysfunction and HCN channelopathy in SHANK3-related autism may inform future therapeutic targets. Understanding the developmental timeline of circuit dysfunction could guide timing of interventions. However, translation from mouse models to human clinical applications requires further research and validation in human studies.

This is a preclinical study using only mouse models, limiting direct translation to human autism. Sample sizes are not reported. The study focuses on one brain region and specific cell types. Long-term behavioral outcomes were not assessed. Findings may be specific to SHANK3-related autism rather than autism more broadly.

Anterior cingulate cortex (ACC) dysfunction is implicated in the cognitive and social deficits associated with autism spectrum disorder (ASD), yet the developmental trajectory of ACC circuit maturation in ASD remains poorly understood. Here, we examined the postnatal development of glutamatergic synaptic connectivity and intrinsic excitability in layer 2/3 pyramidal neurons (PYRs) and Parvalbumin-expressing interneurons (PVINs) in the ACC of mice harboring a deletion in SHANK3 (Shank3B), a well-established genetic cause of autism. We found that ACC PVINs in Shank3Bmice exhibit reduced excitability and in vivo hypoactivity as early as postnatal day 15 (P15) despite receiving normal levels of glutamatergic input. Early PVIN hypoexcitability is associated with decreased feedforward inhibition from the mediodorsal thalamus and reduced hyperpolarization-activated (I) currents mediated by hyperpolarization-activated cyclic nucleotide gated (HCN) channels.

In contrast, PYRs display normal excitability and synaptic input at this stage but already exhibit reduced Icurrents, indicating an early emergence of HCN channel dysfunction in both PYRs and PVINs. By adulthood, both neuron populations undergo marked phenotypic changes, characterized by reduced glutamatergic synaptic input and divergent alterations in excitability. Together, these findings reveal a distinct sequence of early PVIN dysfunction followed by cell-type specific circuit reorganization within ACC layer 2/3 of Shank3Bmice and identify HCN channelopathy and impaired PVIN-mediated inhibition as early pathogenic features of SHANK3-related neurodevelopmental disorders.