ALTERED INHIBITORY MOTIF ORGANIZATION IN MOUSE MODELS OF ALZHEIMER’S DISEASE AND NMDA RECEPTOR HYPOFUNCTION

Hippocampal interneurons are essential for regulating excitability, oscillatory coordination, and cognitive maps stability. Distinct interneuron families—parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP), and Id2-expressing cells—form inhibitory motifs that support theta–gamma coupling and sharp-wave ripples (SWRs), critical for memory encoding and consolidation. Disruption of these motifs has been reported across psychiatric disorders, yet how inhibitory circuit organization diverges or converges across disease remains unclear. Such circuit-level alterations could contribute to cognitive and perceptual disturbances observed in these conditions. Here, we examine the hypothesis that different disorders follow distinct inhibitory trajectories that may converge on a shared endpoint. In Alzheimer’s disease (AD), available evidence suggests early SST dysfunction followed by later PV impairment, whereas models of NMDA receptor hypofunction primarily affect PV-centered circuits from early stages. Using in vivo recordings from APP/PS1 mice and MK-801–treated mice, our preliminary analyses reveal complementary patterns of circuit disruption. APP/PS1 mice exhibit increased pyramidal bursting, altered theta–gamma modulation, reduced ripple-phase locking, and degraded place-field stability, suggestive of early SWR disorganization. In contrast, MK-801 treatment is associated with reduced bursting, weakened theta and gamma modulation, diminished spike synchrony, unreliable SWR recruitment, and reduced spatial information. Classifier-based interneuron analyses further indicate a selective weakening of PV-centered functional connectivity in MK-801 datasets, particularly PV↔pyramidal and PV↔SST interactions, with additional effects involving Id2 interneurons, while SST→pyramidal motifs appear relatively preserved. These preliminary findings suggest that distinct pathological processes may converge on shared disruptions of hippocampal oscillatory coordination.