Levofloxacin-induced seizure susceptibility involves both enhanced glutamatergic and impaired GABAergic synaptic function
Abstract
Levofloxacin (LVFX)-associated seizures are thought to arise from disrupted excitatory-inhibitory balance, but the underlying synaptic mechanisms remain unclear. This study investigated how LVFX alters both glutamatergic and GABAergic transmission to promote neuronal hyperexcitability. We combined in vitro and in vivo approaches using primary cortical neurons treated with LVFX and adult rats administered LVFX. Electrophysiological recordings assessed AMPA receptor (AMPAR)-mediated miniature excitatory postsynaptic currents (mEPSCs) and GABAergic miniature inhibitory postsynaptic currents (mIPSCs). Molecular analyses examined vesicular glutamate transporter 1 (VGluT1) and vesicular GABA transporter (VGAT) expression, along with AMPAR subunit GluA1 trafficking dynamics. Seizure susceptibility was evaluated using magnesium-free conditions in vitro and pentylenetetrazol challenge in vivo. LVFX treatment significantly increased mEPSC frequency and amplitude while decreasing mIPSC frequency, indicating enhanced excitatory and suppressed inhibitory synaptic transmission. These changes were accompanied by upregulated VGluT1 and downregulated VGAT protein expression. The drug specifically altered GluA1 trafficking by decreasing internalization and promoting recycling to the plasma membrane. These synaptic modifications resulted in heightened seizure susceptibility, with LVFX-treated neurons showing earlier epileptiform discharges and pretreated animals exhibiting significantly…
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