IMPAIRED VISUAL FAMILIARITY-EVOKED THETA OSCILLATIONS IN THE HIPPOCAMPUS OF FMR1 KO MICE

Fragile X syndrome (FX), the most common monogenic cause of autism spectrum disorders (ASDs), is characterized by profound disruptions in sensory processing and learning. Previous work has shown that passive visual familiarity is associated with impaired theta (4–8 Hz) oscillations in the primary visual cortex (V1) of Fmr1 knockout (KO) mice. However, it remains unknown whether familiarity-related theta oscillations also emerge during active learning, and how their dynamics differ between wild-type (WT) and Fmr1 KO animals. To address this gap, we performed in vivo Neuropixels recordings from V1 and the hippocampus (HPC) in mice engaged in a Go/No-Go visual discrimination task. We discovered that Fmr1 KO animals exhibited impaired behavioral response suppression during No-Go trials. Electrophysiological analyses revealed that familiarity-evoked theta oscillations in V1 were selectively and significantly reduced in Fmr1 KO mice during No-Go stimulus presentation, consistent with a deficit in memory-guided behavioral inhibition. In addition, theta–gamma phase–amplitude coupling (PAC), an indicator of local circuit integration, was markedly decreased in V1 of Fmr1 KO mice, whereas hippocampal theta power and PAC remained intact. Together, these findings identify a circuit-specific disruption of cortical theta oscillations and cross-frequency coupling in Fragile X syndrome, linking impaired sensory memory representations in V1 to deficits in behavioral regulation during active learning.