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  1. Neuronal Kv7/Potassium Voltage-Gated Channel Subfamily Q (KCNQ) potassium channels underlie M-current that potently suppresses repetitive and burst firing of action potentials (APs). They are mostly heterotetramers of Kv7.2 and Kv7.3 subunits in the hippocampus and cortex, the brain regions important for cognition and behavior. Underscoring their critical roles in inhibiting neuronal excitability, autosomal dominantly inherited mutations in Potassium Voltage-Gated Channel Subfamily Q Member 2 (KCNQ2) and Potassium Voltage-Gated Channel Subfamily Q Member 3 (KCNQ3) genes are associated with benign familial neonatal epilepsy (BFNE) in which most seizures spontaneously remit within months without cognitive deficits.De novomutations inKCNQ2also cause epileptic encephalopathy (EE), which is characterized by persistent seizures that are often drug refractory, neurodevelopmental delay, and intellectual disability. Heterozygous expression of EE variants ofKCNQ2is recently shown to induce spontaneous seizures and cognitive deficit in mice, although it is unclear whether this cognitive deficit is caused directly by Kv7 disruption or by persistent seizures in the developing brain as a consequence of Kv7 disruption. In this study, we examined the role of Kv7 channels in learning and memory by behavioral phenotyping of theKCNQ2+/−mice, which lack a single copy ofKCNQ2but dos not display spontaneous seizures. We found that bothKCNQ2+/−and wild-type (WT) mice showed comparable nociception in the tail-flick assay and fear-induced learning and memory during a passive inhibitory avoidance (IA) test and contextual fear conditioning (CFC). Both genotypes displayed similar object location and recognition memory. These findings together provide evidence that heterozygous loss ofKCNQ2has minimal effects on learning or memory in mice in the absence of spontaneous seizures.

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  2. Homeostatic plasticity encompasses the mechanisms by which neurons stabilize their synaptic strength and excitability in response to prolonged and destabilizing changes in their network activity. Prolonged activity blockade leads to homeostatic scaling of action potential (AP) firing rate in hippocampal neurons in part by decreased activity of N-Methyl-D-Aspartate receptors and subsequent transcriptional down-regulation of potassium channel genes includingKCNQ3which encodes Kv7.3. Neuronal Kv7 channels are mostly heterotetramers of Kv7.2 and Kv7.3 subunits and are highly enriched at the axon initial segment (AIS) where their current potently inhibits repetitive and burst firing of APs. However, whether a decrease in Kv7.3 expression occurs at the AIS during homeostatic scaling of intrinsic excitability and what signaling pathway reducesKCNQ3transcript upon prolonged activity blockade remain unknown. Here, we report that prolonged activity blockade in cultured hippocampal neurons reduces the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) followed by a decrease in the activation of brain-derived neurotrophic factor (BDNF) receptor, Tropomyosin receptor kinase B (TrkB). Furthermore, both prolonged activity blockade and prolonged pharmacological inhibition of ERK1/2 decreaseKCNQ3andBDNFtranscripts as well as the density of Kv7.3 and ankyrin-G at the AIS. Collectively, our findings suggest that a reduction in the ERK1/2 activity and subsequent transcriptional down-regulation may serve as a potential signaling pathway that links prolonged activity blockade to homeostatic control of BDNF-TrkB signaling and Kv7.3 density at the AIS during homeostatic scaling of AP firing rate.

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  3. null (Ed.)