CRTC1 knockdown in the marmoset visual cortex induces neuronal IEG overexpression, HFOs, and neurodegeneration

CRTC1 is highly expressed in the brain and functions as a coactivator of CREB, regulating transcription of genes essential for neuronal function and plasticity. To elucidate its role in the primate cortex, we performed CRTC1 knockdown using short hairpin RNA (shRNA) in the visual cortex (V1) of common marmosets (Callithrix jacchus). Unexpectedly, the knockdown caused widespread cFOS induction beyond the injection site. Concurrently, reduced NeuN expression, appearance of cell death markers, increased glial markers, and glial scarring were observed around the lesion. Longitudinal electrocorticography revealed transient perturbations in high-frequency oscillations (HFOs) across widespread cortical areas. MRI and histology confirmed lesion formation in the temporal lobe within months, followed by progressive degeneration near the injection site. Notably, glial and cell death marker changes appeared within one month, preceding or coinciding with IEG induction. These findings suggest that CRTC1 may exert neuroprotective effects by restraining neuronal hyperexcitability. We further discuss molecular pathways linking CRTC1 knockdown to sequential cell death and hyperexcitability leading to IEG and HFO induction. Our results provide new insights into the mechanisms underlying HFO regulation and neuroprotection in the primate cortex following localized knockdown of a transcriptional coactivator.