Presynaptic GABAB Receptors Regulate Retinohypothalamic Tract Synaptic Transmission by Inhibiting Voltage-Gated Ca Channels

Moldavan, Mykhaylo G., Robert P. Irwin, and Charles N. Allen. Presynaptic GABAB receptors regulate retinohypothalamic tract synaptic transmission by inhibiting voltage-gated Ca channels. J Neurophysiol 95: 3727–3741, 2006; doi:10.1152/jn.00909.2005. Presynaptic GABAB 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 Ca -sensitive fluorescent probes within RHT terminals were used to examine GABAB-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 voltagedependent Ca channels, but not L-type, reduced the EPSC amplitude by 66, 36, 32, and 18% of control, respectively. Joint application of multiple Ca channel blockers inhibited the EPSCs less than that predicted, consistent with a model in which multiple Ca 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 Ca influx and resting Ca 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 Ba 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 Ca channels, and possibly by activation of 4-AP–sensitive K channels, but not by inhibition of Rand L-type Ca channels or by Kir3 channel activation.