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 (PKCε) regulates behavioural responses to ethanol and plays a role in anxiety‐like behaviour, but knowledge is limited on downstream substrates of PKCε that contribute to these behaviours. We recently identified brain‐specific serine/threonine‐protein kinase 1 (BRSK1) as a substrate of PKCε. Here, we test the hypothesis that BRSK1 mediates responses to ethanol and anxiety‐like behaviours that are also PKCε dependent. We used in vitro kinase assays to further validate BRSK1 as a substrate of PKCε 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 PKCε at a residue identified in a chemical genetic screen of PKCε 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 PKCε that mediates some PKCε‐dependent responses to ethanol in a sex‐specific manner and plays a role distinct from PKCε in anxiety‐like behaviour. Protein kinase C epsilon (PKCε) signalling is linked to behavioural responses to ethanol andanxiety‐like behaviour. Here, we used knockout mice to evaluate the role of a PKCε 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.