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Presynaptic GABA_B Receptors Regulate Retinohypothalamic Tract Synaptic Transmission by Inhibiting Voltage-Gated Ca²⁺ Channels

¹Center for Research on Occupational and Environmental Toxicology and ²Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon

Submitted 31 August 2005; accepted in final form 25 February 2006

Presynaptic GABA_B receptor activation inhibits glutamate release from retinohypothalamic tract (RHT) terminals in the suprachiasmatic nucleus (SCN). Voltage-clamp whole cell recordings from rat SCN neurons and optical recordings of Ca²⁺-sensitive fluorescent probes within RHT terminals were used to examine GABA_B-receptor modulation of RHT transmission. Baclofen inhibited evoked excitatory postsynaptic currents (EPSCs) in a concentration-dependent manner equally during the day and night. Blockers of N-, P/Q-, T-, and R-type voltage-dependent Ca²⁺ channels, but not L-type, reduced the EPSC amplitude by 66, 36, 32, and 18% of control, respectively. Joint application of multiple Ca²⁺ channel blockers inhibited the EPSCs less than that predicted, consistent with a model in which multiple Ca²⁺ channels overlap in the regulation of transmitter release. Presynaptic inhibition of EPSCs by baclofen was occluded by -conotoxin GVIA (72%), mibefradil (52%), and -agatoxin TK (15%), but not by SNX-482 or nimodipine. Baclofen reduced both evoked presynaptic Ca²⁺ influx and resting Ca²⁺ concentration in RHT terminals. Tertiapin did not alter the evoked EPSC and baclofen-induced inhibition, indicating that baclofen does not inhibit glutamate release by activation of Kir3 channels. Neither Ba²⁺ nor high extracellular K⁺ modified the baclofen-induced inhibition. 4-Aminopyridine (4-AP) significantly increased the EPSC amplitude and the charge transfer, and dramatically reduced the baclofen effect. These data indicate that baclofen inhibits glutamate release from RHT terminals by blocking N-, T-, and P/Q-type Ca²⁺ channels, and possibly by activation of 4-AP–sensitive K⁺ channels, but not by inhibition of R- and L-type Ca²⁺ channels or by Kir3 channel activation.

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