KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia

Abstract

Overexpression in humans of KCNH2-3.1, which encodes a primate-specific and brain-selective isoform of the human ether-a-go-go-related (hERG) potassium channel, is associated with impaired cognition, inefficient neural processing, and schizophrenia. Here, we describe a new mouse model that incorporates the KCNH2-3.1 molecular phenotype. KCNH2-3.1 transgenic mice are viable and display normal sensorimotor behaviors. However, they show alterations in neuronal structure and microcircuit function in the hippocampus and prefrontal cortex, areas affected in schizophrenia. Specifically, in slice preparations from the CA1 region of the hippocampus, KCNH2-3.1 transgenic mice have fewer mature dendrites and impaired theta burst stimulation long-term potentiation (TBS-LTP). Abnormal neuronal firing patterns characteristic of the fast deactivation kinetics of the KCNH2-3.1 isoform were also observed in prefrontal cortex. Transgenic mice showed significant deficits in a hippocampal-dependent object location task and a prefrontal cortex-dependent T-maze working memory task. Interestingly, the hippocampal-dependent alterations were not present in juvenile transgenic mice, suggesting a developmental trajectory to the phenotype. Suppressing KCNH2-3.1 expression in adult mice rescues both the behavioral and physiological phenotypes. These data provide insight into the mechanism of association of KCNH2-3.1 with variation in human cognition and neuronal physiology and may explain its role in schizophrenia.

Impaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective

“…However, there may also be mutations associated with schizophrenia that might directly increase cortical excitability. For example, alterations in several genes implicated in schizophrenia risk, including reductions in transcription factor 4 (43), 15q13.3 microdeletion (44) or increases in hERG (45) or CACNA1c (46), might contribute to schizophrenia risk by increasing cortical excitability. Second, pyramidal neurons may compensate for deficits in glutamatergic input by upregulating their excitability.…”

Biologically relevant subgroups within the schizophrenia syndrome

“…The detected effect of the rs3800779 polymorphism is in line with its previously reported functional effects: the A allele has been associated with an increased expression of the KCNH2-3.1 brain isoform 416 , which confers specific electrical properties to the neuron, like higher firing rate and faster deactivation 418 . These properties might affect directly the spread of action potentials and consequently the coordination and communication between distant group of neurons.…”

“…Also, this SNP is predicted to alter a regulatory motif, with the A allele showing lower affinity for a transcription factor (PAX-5) that is involved in neurodevelopment. Such data point towards a putative molecular mechanism underlying the previously described impact of the rs3800779 risk allele on an increased KCNH2 expression and a higher firing rate and faster deactivation 418 Our study has some limitations, principally the sample size, although Arnedo 58 argued that the low replication rate in genetic studies is not due to small sample sizes but to complex genetic and phenotypic architecture. Accordingly, despite the selected genes and SNPs have been consistently associated with schizophrenia, the polygenic nature of the disorder and the minor effect of common genetic variants limit the power of our sample.…”

Connectome Disconnectivity and Cortical Gene Expression in Patients With Schizophrenia

“…Animal models represent a valuable tool for studying the underlying genetic mechanisms for brain phenotypes (26,27).…”