Disruption of the Autism-Associated Pcdh9 Gene Leads to Transcriptional Alterations, Synapse Overgrowth, and...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Protocadherin 9 (PCDH9) is implicated in neurodevelopmental and psychiatric disorders like Autism Spectrum Disorder (ASD) and Major Depressive Disorder (MDD).
• Previous studies show Pcdh9 deletion causes neuronal defects and cognitive impairments in mice.
• The precise synaptic and molecular mechanisms of PCDH9 in the brain remain largely unexplored.

Purpose of the Study:

• To comprehensively investigate the role of PCDH9 in the male mouse hippocampus.
• To elucidate the synaptic and molecular mechanisms underlying PCDH9's function.
• To understand PCDH9's impact on brain pathology and hippocampal circuits.

Main Methods:

• Ultrastructural, biochemical, transcriptomic (single-nucleus RNA-seq), electrophysiological, and network analyses were performed on Pcdh9 knockout (KO) mouse hippocampi.
• Localization of PCDH9 at glutamatergic synapses was examined.
• Synaptic morphology, gene expression, and neuronal activity were assessed.

Main Results:

• PCDH9 localizes to glutamatergic synapses, with expression peaking during early postnatal synaptogenesis.
• Pcdh9 KO neurons exhibit enlarged presynaptic terminals and postsynaptic densities (PSDs) in the CA1 region.
• Synapse overgrowth is associated with upregulated synaptic genes and dysregulation of the SHANK2/CORTACTIN pathway, leading to increased excitatory postsynaptic currents and reduced network activity.

Conclusions:

• PCDH9 plays a critical role in regulating the morphology and function of hippocampal CA1 excitatory synapses.
• PCDH9 modulates glutamatergic transmission and hippocampal network activity.
• These findings reveal molecular and synaptic mechanisms linking PCDH9 to neurodevelopmental disorders and associated cognitive deficits.