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Mutations of large conductance Ca2+- and voltage-activated K+ channels (BK) are associated with cognitive impairment. Here we report that CA1 pyramidal neuron-specific conditional BK knock-out (cKO) mice display normal locomotor and anxiety behavior. They do, however, exhibit impaired memory acquisition and retrieval in the Morris Water Maze (MWM) when compared to littermate controls (CTRL). In line with cognitive impairment in vivo, electrical and chemical long-term potentiation (LTP) in cKO brain slices were impaired in vitro. We further used a genetically encoded fluorescent K+ biosensor and a Ca2+-sensitive probe to observe cultured hippocampal neurons during chemical LTP (cLTP) induction. cLTP massively reduced intracellular K+ concentration ([K+]i) while elevating L-Type Ca2+ channel- and NMDA receptor-dependent Ca2+ oscillation frequencies. Both, [K+]i decrease and Ca2+ oscillation frequency increase were absent after pharmacological BK inhibition or in cells lacking BK. Our data suggest that L-Type- and NMDAR-dependent BK-mediated K+ outflow significantly contributes to hippocampal LTP, as well as learning and memory. [ABSTRACT FROM AUTHOR]

Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated [Na.sup.+] channel [Na.sub.V]1.1 predominantly expressed in inhibitory interneurons. Homozygous [Scn1a.sup.L1649Q] knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous [Scn1a.sup.L1649Q] knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired [Na.sup.+]*-channel inactivation and increased ramp [Na.sup.+] currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using [K.sup.+]-sensitive electrodes revealed an increase in extracellular [K.sup.+] in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous [Scn1a.sup.L1649Q] knock-in mice was partially rescued by GS967, a blocker of persistent [Na.sup.+] currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD., Introduction With a prevalence of 10% to 15% in the general population, migraine is one of the most common neurological diseases (1, 2) and is rated as one of the [...]