K_v7 (KCNQ) channel openers normalize central 2‐deoxyglucose uptake in a mouse model of mania and increase prefrontal cortical and hippocampal serine‐9 phosphorylation levels of GSK3β

Abstract

J. Neurochem. (2012) 121, 373–382. Abstract Several metabolic neuroimaging studies have indicated that bipolar patients with mania exhibit alterations in metabolic activity, suggesting that perturbations in corticolimbic function contribute to the functional deficits associated with the disease. Because pharmacological stimulation of Kv7 channel function has shown anti‐manic like efficacy in the D‐amphetamine and chlordiazepoxide (AMPH+CDP) induced hyperactivity mouse model of mania, we addressed whether this effect of Kv7 channels could be associated with changes in cerebral [14C]2‐deoxyglucose (2‐DG) uptake, a surrogate marker of brain metabolic activity. Acute administration of the Kv7 channel modulators, retigabine (pan Kv7.2‐Kv7.5 channel opener) and ICA‐27243 (Kv7.2/Kv7.3 channel‐preferring opener) reduced 2‐DG uptake in several mouse forebrain structures with a brain regional signature similar to the mood stabilizers, lithium and valproate. Combined administration of AMPH+CDP enhanced 2‐DG uptake in the striatum, cortex and thalamus, and both retigabine and ICA‐27243 fully prevented this stimulatory effect of AMPH+CDP. In addition, both Kv7 channel openers dose‐dependently increased phospho‐serine‐9 levels of GSK3β in the prefrontal cortex and hippocampus, a common molecular mechanism shared by anti‐manic drugs. In combination, these data emphasize the potential of Kv7 channel openers in the treatment of bipolar disorder, and suggest that heteromeric Kv7.2/Kv7.3 channels may present a novel anti‐manic therapeutic target.

Major channels involved in neuropsychiatric disorders and therapeutic perspectives

“…Inhibition of the hippocampal M-current has been proposed as a general strategy to improve cognitive performance ( Fontan-Lozano et al, 2011); on the other hand M-current openers in prefrontal cortex and hippocampus resulted helpful in mouse model of BPD and schizophrenia. These pre-clinical data indicate that M-current activation restores several key signaling pathways in psychosis similarly to standard drugs, like lithium and valproate ( Kristensen et al, 2012). Kir channels are molecular targets of several antidepressants, thus suggesting that these channels may contribute to the therapeutic action (or adverse effect) of these drugs ( Ohno et al, 2007; Furutani et al, 2009).…”

“…Potassium channels have been proposed to play a role in mechanisms of neural plasticity which are altered in various psychiatric disorders, especially in hippocampus ( Askland, 2006; Fontan-Lozano et al, 2011; Shah et al, 2011; Kristensen et al, 2012). Multiple linkage and association studies have suggested chromosome 8q24 as a promising candidate region for BPD ( Park et al, 2004; Zandi et al, 2008).…”

“…Indeed, pharmacological stimulation of heteromeric Kv7.2/Kv7.3 channels showed promising results in an amphetamine and chlordiazepoxide induced hyperactivity model of mania ( Redrobe and Nielsen, 2009). In addition, neuroimaging studies in bipolar patients with mania revealed alterations in metabolic activity in corticolimbic areas and demonstrated that Kv7 channel activation with retigabine and ICA-27243 reduces baseline cerebral glucose metabolic activity ( Kristensen et al, 2012). These two Kv7 channel openers dose-dependently increased GSK3β in the prefrontal cortex and hippocampus, regions implicated in the emotional and cognitive aspects of mental illness.…”

Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder

“…It also inhibits GSK3β which is responsible for the phosphorylation of Kv7.2/Kv7.3, and phosphorylation of these channels suppresses the M-currents to promote neuronal hyperexcitability (Borsotto et al, 2007). Interestingly, ezogabine, which is a recently approved antiepileptic drug (AED) that targets Kv7.2/Kv7.3 channels, has been shown to have mood stabilizing properties in animal models (Dencker et al, 2008; Redrobe and Nielsen, 2009; Dencker and Husum, 2010; Kristensen et al, 2012) and in a small pilot study in humans (Amann et al, 2006). Finally, a previous genetic study found evidence of an association between variants in KCNQ2 and BP (Borsotto et al, 2007), and our group has reported genome-wide significant linkage of BP with chromosome 8q24 in a region that harbors KCNQ3 (Avramopoulos et al, 2004).…”

A review of potassium channels in bipolar disorder

“…One study (Redrobe and Nielsen, 2009) used a mouse model of mania and determined that EZG (a non-selective opener) and ICA-27243 (a selective Kv7.2/3 opener), but not BMS-204352 (a selective Kv7.4–Kv7.5 and Kv7.7/3 heteromer opener) were able to reduce motility in the hyperactive mice, a paradigm for antimanic properties in drugs. In another study employing the D -amphetamine and chlordiazepoxide (AMPH + CDP) mouse model (Kristensen et al, 2012), EZG reduced cerebral glucose metabolic activity while increasing phosphor-serine-9 levels of GSK3β with a brain regional signature that mirrored lithium and valproate.…”