Developmental regulation of thalamus-driven pauses in striatal cholinergic interneurons

Striatal cholinergic interneuron pause response requires Kv1 channels, is absent in dyskinetic mice, and is restored by dopamine D5 receptor inverse agonism

“…Both margatoxin (MgTx) at 30 nM – but not at 3 nM – and dendrotoxin (DTx, 100 nM, a Kv1.1 and Kv1.6 channel blocker) abolished the pause response without changing the spontaneous firing rate or the burst duration (Figure 2A-E). SCIN have a high reserve of Kv7 channels that limit EPSP summation but do not seem to contribute to the sAHP (Paz et al, 2018) or pause response (McGuirt et al, 2022) in adult mice. Consistent with these findings, the pause induced by thalamic stimulation was not reduced by the Kv7 channel blocker XE-991 (10 uM) (Figure 2F-I).…”

“…Previous in vivo and ex vivo studies have shown that dopamine promotes the pause response through D2R-mediated actions (Aosaki et al, 1994a; Watanabe and Kimura, 1998; Deng et al, 2007; Ding et al, 2010), including inhibitory effects on Ih, which could be activated by the pause and contribute to its end (Deng et al, 2007; McGuirt et al, 2022). The pause shortens when D2R endogenous activation is blocked with D2-type receptor antagonists (Aosaki et al, 1994a; Watanabe and Kimura, 1998; Ding et al, 2010) or D2R are genetically eliminated (Kharkwal et al, 2016), and lengthens when D2R are overexpressed in SCIN (Gallo et al, 2022).…”

“…Theories implicating deactivation of Ih current as its primary cause were refuted by experiments demonstrating pause induction after Ih current blockade when the resulting hyperpolarization is corrected by current injection (Zhang et al, 2018). Although Ih likely contributes to a rebound depolarization limiting pause duration (Deng et al, 2007; McGuirt et al, 2022). Further work suggested the involvement of a slow current mediated by Kv7 channels in juvenile mice (Zhang et al, 2018), which is developmentally downregulated and seems to not contribute significantly in the adult (McGuirt et al, 2022; present findings), though SCIN retain a high reserve of Kv7 channels sensitive to activators (Paz et al, 2018).…”

“…Although Ih likely contributes to a rebound depolarization limiting pause duration (Deng et al, 2007; McGuirt et al, 2022). Further work suggested the involvement of a slow current mediated by Kv7 channels in juvenile mice (Zhang et al, 2018), which is developmentally downregulated and seems to not contribute significantly in the adult (McGuirt et al, 2022; present findings), though SCIN retain a high reserve of Kv7 channels sensitive to activators (Paz et al, 2018). Whether this Kv7 channel reserve is recruited under particular conditions not captured in our slice preparation remains to be determined.…”

“…Further evidence suggests that the pause in SCIN arises from intrinsic mechanisms activated by depolarization (Reynolds et al, 2004; Wilson and Goldberg, 2006; Sanchez et al, 2011). Experiments conducted in brain slices demonstrate that the pause that follows stimulation of SCIN excitatory inputs persists even after blocking GABA-A receptors, indicating the involvement of voltage (Kv) or calcium-dependent (KCa) potassium currents, with dopamine likely modulating these currents (Ding et al, 2010; Schulz and Reynolds, 2013; Zhang et al, 2018; McGuirt et al, 2022).…”