KCNQ(1), estrogen and insulin signalling mechanisms in behavioural inflexibility

Behavioural inflexibility is a symptomatic feature of a number of neuropsychiatric disorders, encompassing the maintenance of a behaviour even when no longer appropriate. This ensues from impaired reward-behaviour recognition, inability to unlearn a previously beneficial behaviour or inability to adopt new contingencies. This symptom appears
across disorders including Obsessive-Compulsive Disorder (OCD), autism and others. The voltage-gated potassium channel Kv7.1 (KCNQ1), in addition to insulin signalling were identified as candidate mechanisms based on previous GWAS studies of OCD. KCNQ1 is ubiquitously expressed and contributes to both somatic and central functions including depolarisation-repolarisation balance of neurons, cardiac arrythmia and endocrine functions including, importantly, the regulation of insulin secretion. Here, we aim to better understand the mechanistic input of both the KCNQ1 channel and insulin signalling into both behavioural and mechanistic aspects of behavioural inflexibility. We utilised a mouse model of constitutive KCNQ1 loss, and conducted behavioural, proteomic, electrophysiological and metabolic analyses to better understand the role of this channel in the brain. Additionally, we explored the role of the orthologue KCNQ in sensory sensitivity with the use of a Drosophila model. These analyses show a stark phenotype in the mouse model of KCNQ1 loss including learning and memory deficits, reversal switching changes and altered anxiety and environmental sensitivity. Proteomic changes point to a strong signature of mitochondrial dysfunction, encompassing both respiratory and cell stress-associated signalling. Metabolic Seahorse and electrophysiological synaptic fEPSP measurements also highlight an altered respiration and cell stress response. Other mechanistic signatures relate to inflammation, in particular complement signalling in the periphery. KCNQ mutant Drosophila show a significantly altered response to sensory stress which, crucially, showed partial rescue following metformin treatment. Furthermore, we examined the role of insulin in behavioural changes via behavioural and proteomic analyses of the TALLYHO/JngJ mouse model of Type 2 Diabetes and obesity. These mice displayed changes in attention, reversal switching and reward-inhibition, with proteomic changes suggesting altered mitochondrial function, and inflammation. Crucially, both models converge on compulsive symptomology, and metabolic-inflammatory and synaptogenesis-associated mechanisms. Finally, a comparison across GWAS analyses of compulsive disorders and their comorbidities highlighted estrogen signalling as a potential mechanism to investigate, with Seahorse metabolic analysis suggesting an estrogen-KCNQ1 crosstalk in metabolic regulation. In conclusion, our results indicate that insulin dysregulation and KCNQ1 are candidate mechanisms underlying behavioural inflexibility, converging on mitochondria, immunity and synaptic dynamics.