Minocycline-induced microglial remodeling restores hippocampal NMDA-dependent synaptic plasticity and reduces anxiety-like behavior in juvenile rats with temporal lobe epileptogenesis.

Abstract

Microglial activation and neuroinflammation are recognized as key drivers of synaptic dysfunction in temporal lobe epilepsy (TLE), yet the causal mechanisms linking specific microglial phenotypes to neuronal hyperexcitability remain poorly understood, and clinically viable therapeutic strategies to modulate these processes are urgently needed. Using the lithium-pilocarpine model in young male rats (P21-P28), we demonstrate that a 7-day minocycline treatment (100 → 50 mg/kg, i.p.), initiated immediately following status epilepticus, induces robust and selective microglial morphological remodeling. Quantitative morphometric analysis of Iba1cells revealed a significant shift from activated amoeboid morphology to surveillant ramified phenotypes, without altering microglial density in hippocampal CA1 regions. This structural reorganization correlated with complete functional recovery: electrophysiological recordings showed full restoration of NMDA receptor-dependent long-term potentiation and rescue of NMDAR-mediated currents during high-frequency stimulation. Importantly, these synaptic improvements occurred independently of neuroprotection, as Nissl staining confirmed unchanged neuronal survival in CA1/CA3 subfields. Behavioral assessments at P27 demonstrated significant attenuation of epilepsy-associated anxiety-like behaviors, including reduced self-grooming and normalized exploratory activity in the open field test. Notably, minocycline treatment also attenuated reactive astrogliosis, suggesting coordinated modulation of neuroinflammatory cascades. Our findings demonstrate that short-term minocycline administration induces a structural and functional reprogramming of microglia, which is sufficient to restore hippocampal synaptic plasticity and reduce anxiety in a rat model of TLE. This highlights microglial morphological plasticity as a critical therapeutic target for counteracting epileptogenesis.