Slow changes in Ca²⁺ cause prolonged release from GABAergic retinal amacrine cells

Abstract

The timing of neurotransmitter release from neurons can be modulated by many presynaptic mechanisms. The retina uses synaptic ribbons to mediate slow graded glutamate release from bipolar cells that carry photoreceptor inputs. However, many inhibitory amacrine cells, which modulate bipolar cell output, spike and do not have ribbons for graded release. Despite this, slow glutamate release from bipolar cells is modulated by slow GABAergic inputs that shorten the output of bipolar cells, changing the timing of visual signaling. The time course of light-evoked inhibition is slow due to a combination of receptor properties and prolonged neurotransmitter release. However, the light-evoked release of GABA requires activation of neurons upstream from the amacrine cells, so it is possible that prolonged release is due to slow amacrine cell activation, rather than slow inherent release properties of the amacrine cells. To test this idea, we directly activated primarily action potential-dependent amacrine cell inputs to bipolar cells with electrical stimulation. We found that the decay of GABAC receptor-mediated electrically evoked inhibitory currents was significantly longer than would be predicted by GABAC receptor kinetics, and GABA release, estimated by deconvolution analysis, was inherently slow. Release became more transient after increasing slow Ca(2+) buffering or blocking prolonged L-type Ca(2+) channels and Ca(2+) release from intracellular stores. Our results suggest that GABAergic amacrine cells have a prolonged buildup of Ca(2+) in their terminals that causes slow, asynchronous release. This could be a mechanism of matching the time course of amacrine cell inhibition to bipolar cell glutamate release.

Different types of retinal inhibition have distinct neurotransmitter release properties

“…Unlike the graded membrane depolarization used by bipolar cells, many amacrine cell types rely on action potentials to mediate transmitter release (Bloomfield 1992;Eggers et al 2013;Shields and Lukasiewicz 2003;Taylor 1999). Spikedependent neurotransmitter release is a fast synchronous event that generally involves the rapid increase of intracellular Ca 2ϩ near release sites and subsequent neurotransmitter release to occur within 10 -20 ms (Kaeser and Regehr 2013).…”

“…Spikedependent neurotransmitter release is a fast synchronous event that generally involves the rapid increase of intracellular Ca 2ϩ near release sites and subsequent neurotransmitter release to occur within 10 -20 ms (Kaeser and Regehr 2013). However, previous studies have established that release from amacrine cells can occur asynchronously over several hundred milliseconds after a single stimulus (Borges et al 1995;Eggers et al 2013;Eggers and Lukasiewicz 2006b;Gleason et al 1994). In contrast to the fast local rises in intracellular Ca 2ϩ that mediate synchronous release, slow asynchronous release relies on global increases in intracellular Ca 2ϩ far from the release site (Chung and Raingo 2013;Goda and Stevens 1994;Kaeser and Regehr 2013;Sakaba and Neher 2001;Scheuss et al 2007).…”

Transient receptor potential cation channel, subfamilies V, member 1 (TRPV1) and M, member 1 (TRPM1) contribute to neural signaling in mouse retina.

“…Medium field GABAergic ACs release GABA onto GABAc receptors located in ON BC terminals. In this way, ACs enhance the surround suppression of the ON BC to stimuli larger than the BC receptive field (Eggers & Lukasiewicz, 2010;Eggers et al, 2013;Moore-Dotson et al, 2015).…”

“…Lateral inhibition from GABAergic ACs enhances the BC center surround organization through GABAc receptors. However, other spiking GABAergic and glycinergic ACs serially inhibit the ACs providing surround suppression to BCs (Eggers et al, 2013;Moore-Dotson et al, 2015).…”

“…Further complicating matters, however, is the idea that the responses within these pathways may not be static, but depend on stimulus (Umino et al, 2008;Eggers et al, 2013;Farrow et al, 2013;Grimes et al, 2015). For example, some ON GCs can signal light offset and OFF GCs can signal light onset depending on luminance conditions or stimulus size (Sagdullaev & McCall, 2005;TikidjiHamburyan et al, 2015).…”