Conditional deletion of MDM2 in neurons impairs neuronal homeostasis and cognitive ability.

INTRODUCTION: Murine double minute 2 (MDM2) has been implicated in diverse neurological disorders, yet its precise function in the central nervous system remains poorly defined. OBJECTIVES: This study aimed to elucidate the roles of MDM2 in postnatal forebrain development, synaptic function, and cognition by generating and analyzing a forebrain-specific conditional knockout (cKO) model. METHODS: We generated a forebrain-specific conditional knockout mouse line in which MDM2 was selectively ablated under the control of the CaMKIIα promoter. We employed morphometric analysis, Western blot, whole-cell patch-clamp recordings in hippocampal pyramidal neurons, in vivo two-photon calcium imaging in the primary visual cortex, and behavioral tests (Y-maze, novel object recognition, Morris water maze) to assess memory and learning. RESULTS: MDM2 cKO mice exhibited severe microcephaly, characterized by cortical thinning, hippocampal shrinkage, and reduced neuronal density alongside glial proliferation. Synaptic deficits were evident from reduced synaptic protein levels, dendritic spine loss, and impaired long-term potentiation. Moreover, MDM2-deficient neurons showed intrinsic hyperexcitability. In vivo calcium imaging revealed normal mean response to visual stimulus but impaired cortical computation, with reduced population coding capacity for naturalistic stimuli. Behaviorally, MDM2 cKO mice displayed profound deficits in spatial memory, object recognition, and spatial learning. CONCLUSIONS: Our findings establish MDM2 as a critical regulator of postnatal cortical structure, synaptic plasticity, and cognitive function, highlighting its potential as a therapeutic target for neurodevelopmental disorders with cognitive deficits.