GABA_AReceptor-Mediated Signaling Alters the Structure of Spontaneous Activity in the Developing Retina

Abstract

Ambient GABA modulates firing patterns in adult neural circuits by tonically activating extrasynaptic GABA A receptors. Here, we demonstrate that during a developmental period when activation of GABA A receptors causes membrane depolarization, tonic activation of GABA A receptors blocks all spontaneous activity recorded in retinal ganglion cells (RGCs) and starburst amacrine cells (SACs). Bath application of the GABA A receptor agonist muscimol blocked spontaneous correlated increases in intracellular calcium concentration and compound postsynaptic currents in RGCs associated with retinal waves. In addition, GABA A receptor agonists activated a tonic current in RGCs that significantly reduced their excitability. Using a transgenic mouse in which green fluorescent protein is expressed under the metabotropic glutamate receptor subtype 2 promoter to target recordings from SACs, we found that GABA A receptor agonists blocked compound postsynaptic currents and also activated a tonic current. GABA A receptor antagonists reduced the holding current in SACs but not RGCs, indicating that ambient levels of GABA tonically activate GABA A receptors in SACs. GABA A receptor antagonists did not block retinal waves but did alter the frequency and correlation structure of spontaneous RGC firing. Interestingly, the drug aminophylline, a general adenosine receptor antagonist used to block retinal waves, induced a tonic GABA A receptor antagonist-sensitive current in outside-out patches excised from RGCs, indicating that aminophylline exerts its action on retinal waves by direct activation of GABA A receptors. These findings have implications for how various neuroactive drugs and neurohormones known to modulate extrasynaptic GABA A receptors may influence spontaneous firing patterns that are critical for the establishment of adult neural circuits.

Extrasynaptic glutamate and inhibitory neurotransmission modulate ganglion cell participation during glutamatergic retinal waves

“…4, A-C). Previously, we have shown that inhibition shapes cholinergic waves by decreasing wave frequency via increased shunting inhibition to RGCs through potentiated amacrine cells (Wang et al 2007). Similarly, we found that Gbz/Stry led to a dramatic increase in event frequency, as assessed by both FLII 81 E-1 and Ca 2ϩ imaging (Fig.…”

Extrasynaptic release of GABA and dopamine by retinal dopaminergic neurons

“…Thus, the ubiquitous presence of extracellular GABA may control the excitability of the neural processes in the IPL by acting on metabotropic GABA B receptors, which are widely expressed on amacrine and ganglion cells [59], as well as on synaptic and extrasynaptic ionotropic GABA A and GABA C receptors. In fact, tonic GABAergic currents have been reported in bipolar cell terminals [60,61] and starburst amacrine cells [62]. The IPL is unique in the nervous system because in its five, 10 mm thick strata are segregated the synapsing processes of over 50 different types of neurons, each encoding different parameters of the light stimuli: the glutamatergic synapses connecting OFF-cone bipolars to OFF-ganglion cells in stratum 2 are adjacent to the glutamatergic synapses between ON-cone bipolars and ON-ganglion cells in stratum 3.…”

Early-Stage Waves in the Retinal Network Emerge Close to a Critical State Transition between Local and Global Functional Connectivity

“…4 E), and similar results were obtained in older animals (data not shown). Experimental observations suggest that around day P5 in mouse, GABAergic transmission begins to influence RGC spiking, increases spatial correlations and has subtle effects on wave spatial extent and frequency (Wang et al, 2007;E. Sernagor, unpublished data).GABA has a depolarizing effect at this developmental stage due to elevated [Cl Ϫ ] i , so it is possible that maturation of the GABAergic drive causes an effective synaptic strengthening.…”