Large-conductance calcium-activated potassium (BK) channels regulate respiratory, metabolic and behavioural responses to CO2/pH in mice.

Large-conductance Ca2+-activated K+ (BK) channels regulate excitability across physiological systems, and BK channelopathies cause neurodevelopmental delay, cognitive disability and structural brain malformations. The firing rate response of CO2/pH chemosensitive neurones has been suggested to be modulated by the BK channels' activity, which would function as a 'brake' on the chemosensitive response. Thus, our study examined the role of BK channels in ventilatory, metabolic and behavioural responses under normocapnic and hypercapnic conditions in wild-type (Slo1+/+) and BK channel knockout (Slo1-/-) mice of both sexes during postnatal development. Additionally, the electrophysiological properties and chemosensitivity of locus coeruleus (LC) neurones in Slo1+/+ and Slo1-/- mice of both sexes were studied. Our data show that Slo1-/- mice displayed multiple changes in respiratory and behavioural phenotypes. Across sexes, Slo1-/- animals experienced a higher rate of apnoeic events: females exhibited more spontaneous apnoeas, whereas males showed more post-sigh apnoeas and sighs. Slo1-/- males also demonstrated an exaggerated chewing reflex. Behaviourally, Slo1-/- females spent less time in the periphery and more time in the centre of the open-field arena compared with wild-type females. During the panic-inducing 20% CO2 challenge, both sexes showed reduced defensive responses, including fewer escape jumps. Lastly, LC neurones from Slo1-/- males exhibited an enhanced chemosensitive response to CO2 compared with controls. These findings demonstrate that loss of BK channels disrupts respiratory stability, alters behavioural responses and enhances central CO2 chemosensitivity in an age- and sex-dependent manner. KEY POINTS: Absence of BK channels increases breathing variability and apnoea events during postnatal development. BK channel deletion leads to an augmented hypercapnic ventilatory response during postnatal development in a sex-dependent manner. Loss of BK channels reduces panic-like behavioural responses during panic attack induction. LC neurones lacking BK channels exhibit increased CO2 chemosensitivity in male mice.