Presynaptic GABA(B) autoreceptor modulation of P/Q-type calcium channels and GABA release in rat suprachiasmatic nucleus neurons

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Abstract

GABA is the primary transmitter released by neurons of the suprachiasmatic nucleus (SCN), the circadian clock in the brain. Whereas GABA(B) receptor agonists exert a significant effect on circadian rhythms, the underlying mechanism by which GABA(B) receptors act in the SCN has remained a mystery. We found no GABA(B) receptor-mediated effect on slow potassium conductance, membrane potential, or input resistance in SCN neurons in vitro using whole-cell patch-clamp recording. In contrast, the GABA(B) receptor agonist baclofen (1-100 μM) exerted a large and dose-dependent inhibition (up to 100%) of evoked IPSCs. Baclofen reduced the frequency of spontaneous IPSCs but showed little effect on the frequency or amplitude of miniature IPSCs in the presence of tetrodotoxin. The activation of GABA(B) receptors did not modulate postsynaptic GABA(A) receptor responses. The depression of GABA release by GABA(B) autoreceptors appeared to be mediated primarily through a modulation of presynaptic calcium channels. The baclofen inhibition of both calcium currents and evoked IPSCs was greatly reduced (up to 100%) by the P/Q-type calcium channel blocker agatoxin IVB, suggesting that P/Q-type calcium channels are the major targets involved in the modulation of GABA release. To a lesser degree, N-type calcium channels were also involved. The inhibition of GABA release by baclofen was abolished by a pretreatment with pertussis toxin (PTX), whereas the inhibition of whole- cell calcium currents by baclofen was only partially depressed by PTX, suggesting that G-protein mechanisms involved in GABA(B) receptor modulation at the soma and axon terminal may not be identical. We conclude that GABA(B) receptor activation exerts a strong presynaptic inhibition of GABA release in SCN neurons, primarily by modulating P/Q-type calcium channels at axon terminals.

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Chen, G., & Van den Pol, A. N. (1998). Presynaptic GABA(B) autoreceptor modulation of P/Q-type calcium channels and GABA release in rat suprachiasmatic nucleus neurons. Journal of Neuroscience, 18(5), 1913–1922. https://doi.org/10.1523/jneurosci.18-05-01913.1998

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