Inactivation of GIRK channels weakens the pre‐ and postsynaptic inhibitory activity in dorsal raphe neurons

Abstract

The serotonergic tone of the dorsal raphe (DR) is regulated by 5‐HT 1A receptors, which negatively control serotonergic activity via the activation of G protein‐coupled inwardly rectifying K+ (GIRK) channels. In addition, DR activity is modulated by local GABAergic transmission, which is believed to play a key role in the development of mood‐related disorders. Here, we sought to characterize the role of GIRK2 subunit‐containing channels on the basal electrophysiological properties of DR neurons and to investigate whether the presynaptic and postsynaptic activities of 5‐HT 1A, GABAB, and GABAA receptors are affected by Girk2 gene deletion. Whole‐cell patch‐clamp recordings in brain slices from GIRK2 knockout mice revealed that the GIRK2 subunit contributes to maintenance of the resting membrane potential and to the membrane input resistance of DR neurons. 5‐HT 1A and GABAB receptor‐mediated postsynaptic currents were almost absent in the mutant mice. Spontaneous and evoked GABAA receptor‐mediated transmissions were markedly reduced in GIRK2 KO mice, as the frequency and amplitude of spontaneous IPSCs were reduced, the paired‐pulse ratio was increased and GABA‐induced whole‐cell currents were decreased. Similarly, the pharmacological blockade of GIRK channels with tertiapin‐Q prevented the 5‐HT 1A and GABAB receptor‐mediated postsynaptic currents and increased the paired‐pulse ratio. Finally, deletion of the Girk2 gene also limited the presynaptic inhibition of GABA release exerted by 5‐HT 1A and GABAB receptors. These results indicate that the properties and inhibitory activity of DR neurons are highly regulated by GIRK2 subunit‐containing channels, introducing GIRK channels as potential candidates for studying the pathophysiology and treatment of affective disorders.

Chronic antidepressant potentiates spontaneous activity of dorsal raphe serotonergic neurons by decreasing GABAB receptor-mediated inhibition of L-type calcium channels

“…Whereas both serotonergic and GABAergic neurons in the DRN express GABA B receptors, our analysis with intracellular drug application suggest that the activation of postsynaptic GABA B receptors plays an essential role in the inhibition of serotonergic neurons. While GABA B receptor agonist-induced activation of GIRK channels and subsequent membrane hyperpolarization are well-studied 11 , 31 , 40 , GABA B antagonist-induced depolarization was subtle in present study, suggesting that inactivation of GIRK channels had little effects on GABA B antagonist-induced activation of serotonergic firing activity. However, additional researches will be required to investigate the downstream signalings of GABA B receptors and how those signalings control serotonergic activity.…”

“…Evidence suggests that GABA B receptor-mediated activation of G protein-coupled inwardly-rectifying K + (GIRK) channels inhibits serotonergic neurons through hyperpolarization of the RMP 31 . However, there was no difference in pseudo RMP between the drug-naïve and citalopram-treated groups (Supplementary Table S2 ), indicating that chronic citalopram-induced activation of serotonergic neurons was not due to hyperpolarization of RMP.…”

“…It is well-known that the local GABAergic inhibition decreases serotonergic activity 4 , 10 . Besides ionotropic GABA A receptors, metabotropic GABA B receptors are also expressed in serotonergic neurons 31 . Whereas both serotonergic and GABAergic neurons in the DRN express GABA B receptors, our analysis with intracellular drug application suggest that the activation of postsynaptic GABA B receptors plays an essential role in the inhibition of serotonergic neurons.…”

Selective vulnerability of dorsal raphe‐medial prefrontal cortex projection neurons to corticosterone‐induced hypofunction

“…This suggests that in vivo the CORT‐treated mPFC‐projecting neurons would be less responsive to afferent synaptic input than vehicle‐treated neurons. The effect of CORT on the IR of mPFC‐projecting neurons may be the result of greater ion channel conductance (McCormick, ) and the lack of a concurrent change in RMP suggests that increased chloride conductance may be responsible (Jin et al., ; Kirby et al., ; Llamosas, Ugedo, & Torrecilla, ). GABA‐ergic neurons in the periaqueductal gray are important regulators of DR 5‐HT activity (Fu et al., ; Soiza‐Reilly & Commons, ).…”

Selective Modulation of K+ Channel Kv7.4 Significantly Affects the Excitability of DRN 5-HT Neurons

“…Neuronal activity is controlled by the intrinsic activity of ion channels as well as by the regulatory transmitters and hormones. For 5-HT neurons, some K + channels, including SK channels (Crespi, 2010 ; Sargin et al, 2016 ), TREK1 channels (Ye et al, 2015 ) and Kir3/GIRK channels (Llamosas et al, 2015 , 2017 ; Montalbano et al, 2015 ) have been suggested as playing important roles in controlling the intrinsic neuronal activity, and modulating these channels may alleviate emotional disorders. For example, up-regulation of SK3 channels in serotonin-producing neurons are responsible for greatly reduced activity in these neurons from a model of isolated mice; blocking these inhibitory SK3 channels restores normal activity in the serotonin-producing cells and alleviates the depressive symptoms of the isolated mice (Sargin et al, 2016 ).…”