Neuron-specific Drp1 deletion exacerbates hippocampal synaptic dysfunction and spatial memory impairment during high-fat diet-induced metabolic stress

High-fat diet (HFD)-induced metabolic dysfunction is associated with hippocampal injury and cognitive impairment, but the neuronal factors that determine susceptibility to these abnormalities remain unclear. Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission that supports neuronal and synaptic function. Here, we investigated whether neuron-specific Drp1 deletion aggravates hippocampal dysfunction in mice exposed to an HFD for 6 months. HFD feeding induced metabolic abnormalities. Compared with HFD-fed wild-type mice, HFD-fed neuron-specific Drp1 knockout (Drp1cKO) mice showed lower brain weight and greater spatial-memory impairment. In the hippocampus, Drp1cKO was associated with reduced CA1 mushroom-spine density, lower synapsin1, Homer1, and glutaminase1 levels, and fewer ultrastructurally identifiable synapses. Whole-cell recordings from CA1 pyramidal neurons revealed larger evoked excitatory postsynaptic currents, a lower paired-pulse ratio, and altered input resistance in HFD-fed Drp1cKO mice, whereas resting membrane potential was unchanged. HFD-fed Drp1cKO mice also showed increased TUNEL-positive cells and ProteoStat signal, accompanied by reactive glial alterations in the hippocampus, including reduced microglial ramification and changes in GFAP, galectin-3, and Iba-1 expression. In primary hippocampal neurons, Drp1 knockdown reduced cell viability, increased LDH release and mitochondrial superoxide-associated fluorescence, decreased mitochondrial membrane potential, and reduced apposed Synapsin I⁺/Homer1⁺ puncta under control and high-glucose conditions. Together, these findings indicate that neuronal Drp1 deficiency is associated with mitochondrial abnormalities, synaptic structural and functional alterations, cellular injury, reactive glial changes, and impaired memory during HFD-induced metabolic stress. Maintenance of Drp1-dependent mitochondrial dynamics may contribute to hippocampal resilience under chronic metabolic stress.