Brimonidine enhances inhibitory postsynaptic activity of OFF- and ON-type retinal ganglion cells in a Wistar rat chronic glaucoma model.

Glaucoma is a multifactorial disease in which retinal ganglion cells (RGCs) undergo excitotoxic damage, leading to their degeneration. The α2-adrenoceptor (α2-AR) agonist brimonidine exerts a neuroprotective effect by regulating postsynaptic excitatory N- methyl-D-aspartate (NMDA) receptor activity in RGCs. However, researchers have not clearly determined whether or how brimonidine regulates inhibitory synaptic transmission in rat models of chronic glaucoma. Whole-cell voltage-clamp and current-clamp recordings were performed in ON- and OFF-type RGCs in retinal slices. Brimonidine directly and acutely enhanced γ-aminobutyric acidergic (GABAergic) transmission mediated by ionotropic GABA A receptors in ON- and OFF-type RGCs in rat retinal slices; this effect occurred at the synaptic terminals and was independent of action potentials and multi-synaptic connections. The highly selective α2-AR antagonist yohimbine blocked the effects of brimonidine. Regarding the postsynaptic GABA receptor sensitivity, brimonidine also increased the amplitude of the GABA-induced current. Additionally, compared to RGCs from the control group, the frequencies and amplitudes of spontaneous excitatory postsynaptic currents (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) did not change after brimonidine gravity perfusion. Brimonidine significantly decreased the spontaneous firing frequency of rat RGCs with intact synaptic inputs and decreased the resting membrane potential of RGCs, changes that were blocked by the highly selective GABA A receptor antagonist SR95531. SR95531 alone increased spontaneous action potentials and the resting membrane potential. Based on these findings, an α2-AR agonist facilitated the frequency of the GABAergic inhibitory postsynaptic currents (IPSCs), directly increased the amplitude of the postsynaptic GABA-induced current (GABA receptor reactivity/sensitivity), suppressed the firing frequency of spontaneous action in RGCs with intact synaptic inputs and decreased the resting membrane potential of RGCs, thus deactivating RGCs from the neural network level and reducing the excitotoxic damage occurring during the pathological process of chronic glaucoma. • Brimonidine directly and acutely enhances GABAergic transmission. • Brimonidine increases the amplitude of GABA-induced currents in RGCs. • Brimonidine has no effect on the sEPSCs and mEPSCs. • Brimonidine decreases the fring frequency and the resting membrane potential of RGCs. • The effects of brimonidine were blocked by yohimbine and SR95531. [ABSTRACT FROM AUTHOR]