Abstract
Acetylcholine (ACh) is a major retinal neurotransmitter that modulates visual processing through a large repertoire of cholinergic receptors expressed on different retinal cell types. ACh is released from starburst amacrine cells (SACs) under scotopic conditions, but its effects on cells of the rod pathway have not been investigated. Using whole-cell patch clamp recordings in slices of rat retina, we found that ACh application triggers GABA release onto rod bipolar (RB) cells. GABA was released from A17 amacrine cells and activated postsynaptic GABAA and GABAC receptors in RB cells. The sensitivity of ACh-induced currents to nicotinic ACh receptor (nAChR) antagonists (TMPH ~ mecamylamine > erysodine > DhβE > MLA) together with the differential potency of specific agonists to mimic ACh responses (cytisine >> RJR2403 ~ choline), suggest that A17 cells express heteromeric nAChRs containing the β4 subunit. Activation of nAChRs induced GABA release after Ca2+ accumulation in A17 cell dendrites and varicosities mediated by L-type voltage-gated calcium channels (VGCCs) and intracellular Ca2+ stores. Inhibition of acetylcholinesterase depolarized A17 cells and increased spontaneous inhibitory postsynaptic currents in RB cells, indicating that endogenous ACh enhances GABAergic inhibition of RB cells. Moreover, injection of neostigmine or cytisine reduced the b-wave of the scotopic flash electroretinogram (ERG), suggesting that cholinergic modulation of GABA release controls RB cell activity in vivo. These results describe a novel regulatory mechanism of RB cell inhibition and complement our understanding of the neuromodulatory control of retinal signal processing.
Highlights
Nicotinic acetylcholine receptors are widely distributed throughout the central nervous system and play essential roles in learning, cognition and addiction (Dani and Bertrand, 2007)
We have found that GABA release from A17 cells can be elicited by activation of nicotinic ACh receptor (nAChR) and that this modulation regulates rod bipolar (RB) cell activity, a new mechanism by which retinal circuits shape visual responses under low light conditions
Pharmacological analysis revealed that ACh-evoked currents were generated by the activation of GABAA (77 ± 6% of control amplitude after SR95531 10 μM, n = 12, p = 0.008) and GABAC receptors (29 ± 3.3% of control after TPMPA 50 μM, n = 10, p = 0.0025; 6.2 ±1.4% of control with SR95531 and TPMPA combined, n = 8, p = 0.005, FIGURE 1 | ACh induces GABA release from A17 cells onto rod bipolar cells. (A) Left, image of a rod bipolar (RB) cell filled with Lucifer yellow during whole-cell patch clamp recordings
Summary
Nicotinic acetylcholine receptors are widely distributed throughout the central nervous system and play essential roles in learning, cognition and addiction (Dani and Bertrand, 2007). Central nAChRs are pentameric cationic channels assembled as homomers of α7–α9 subunits or by combinations of α2–α6 and β2–β4 subunits (Millar and Gotti, 2009). This heterogeneity endows nAChRs with different physiological and pharmacological properties and diverse functional roles in neuronal networks (Mansvelder et al, 2006; Dani and Bertrand, 2007; Albuquerque et al, 2009). ACh is synthesized and released from starburst amacrine cells (SACs) that form narrowly defined cholinergic plexuses in the inner plexiform layer (IPL) (Voigt, 1986). Activation of nAChRs modulates the ON bipolar cell-dependent b-wave of the electroretinogram (ERG) (Jurklies et al, 1996; Varghese et al, 2011; Moyano et al, 2013), suggesting that ACh may influence signal transmission at stages preceding GC activation, but its specific targets and mechanisms of action remain largely unknown
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