Brain-specific serine/threonine-protein kinase 1 is a substrate of protein kinase C epsilon involved in sex-specific ethanol and anxiety phenotypes

Protein kinase C epsilon (PKC epsilon) regulates behavioural responses to ethanol and plays a role in anxiety-like behaviour, but knowledge is limited on downstream substrates of PKC epsilon that contribute to these behaviours. We recently identified brain-specific serine/threonine-protein kinase 1 (BRSK1) as a substrate of PKC epsilon. Here, we test the hypothesis that BRSK1 mediates responses to ethanol and anxiety-like behaviours that are also PKC epsilon dependent. We used in vitro kinase assays to further validate BRSK1 as a substrate of PKC epsilon and used Brsk1-/- mice to assess the role of BRSK1 in ethanol- and anxiety-related behaviours and in physiological responses to ethanol. We found that BRSK1 is phosphorylated by PKC epsilon at a residue identified in a chemical genetic screen of PKC epsilon substrates in mouse brain. Like Prkce-/- mice, male and female Brsk1-/- mice were more sensitive than wild-type to the acute sedative-hypnotic effect of alcohol. Unlike Prkce-/- mice, Brsk1-/- mice responded like wild-type to ataxic doses of ethanol. Although in Prkce-/- mice ethanol consumption and reward are reduced in both sexes, they were reduced only in female Brsk1-/- mice. Ex vivo slice electrophysiology revealed that ethanol-induced facilitation of GABA release in the central amygdala was absent in male Brsk1-/- mice similar to findings in male Prkce-/- mice. Collectively, these results indicate that BRSK1 is a target of PKC epsilon that mediates some PKC epsilon-dependent responses to ethanol in a sex-specific manner and plays a role distinct from PKC epsilon in anxiety-like behaviour. Protein kinase C epsilon (PKC epsilon) signalling is linked to behavioural responses to ethanol andanxiety-like behaviour. Here, we used knockout mice to evaluate the role of a PKC epsilon substrate,brain-specific serine/threonine-protein kinase 1 (BRSK1), in these behaviours. We found thatBRSK1 influences these behaviours in a sex-specific manner; notably, ethanol consumption andreward were reduced in female BRSK1 knockout mice, while anxiety-like behaviour wasincreased in male BRSK1 knockout mice. image