Neuronal Drp1 deficiency promotes hippocampal neurodegeneration and synaptic loss through mitochondrial stress and altered TASK-1 signaling in the middle-aged mice

Aging enhances neuronal mitophagy in the hippocampus, but how impaired mitochondrial fission shapes this process and drives neuronal death and synaptic failure remains unclear. Here, we investigated how neuron-specific deletion of dynamin-related protein 1 (Drp1) affects hippocampal mitophagy, neuronal survival, synaptic architecture, microglial activation, potassium channel activity, and memory function in 12-month-old mice. Using mt-Keima transgenic mice, we first confirmed that hippocampal mitophagy progressively increases in 12-month-old mice compared with 6-month-old mice. In 12-month-old neuron‑specific Drp1 knockout (Drp1cKO) mice, we observed marked hippocampal neurodegeneration, increased neuronal death, tau hyperphosphorylation, and robust microglial activation, accompanied by profound reductions in dendritic spine density, loss of synapses, and impaired spatial learning and memory. Electrophysiological recordings at Schaffer collateral–CA1 synapses revealed enhanced excitatory synaptic transmission and reduced input resistance in Drp1cKO neurons, coincident with upregulation of TWIK‑related acid‑sensitive K + channel‑1 (TASK‑1). In primary hippocampal neurons, pharmacological inhibition of Drp1 recapitulated mitochondrial depolarization, reduced oxygen consumption, and synaptic loss, whereas TASK‑1 overexpression or activation partially restored mitochondrial function and synaptic puncta. Collectively, these data show that neuronal Drp1 deficiency is associated with mitochondrial dysfunction, altered autophagy-lysosome-related mitochondrial handling, neurodegeneration, synaptic loss, and memory impairment in the aging hippocampus. TASK1 upregulation may represent a compensatory mechanism that partially limits mitochondrial and synaptic dysfunction under Drp1-deficient conditions.