Schizophrenia is a devastating psychiatric illness afflicting approximately 1% of the worlds population. Currently, the disease mechanism is poorly understood and the pharmacological interventions relieve only some of the symptoms. Schizophrenia is highly heritable and genetic factors contribute to about 65-80% of the liability to the illness. However, the genetic etiology is complex and remains largely unknown.
Potassium channels are key determinants of neuronal excitability. Kv2.1 is a widely-expressed voltage-gated potassium channel α-subunit. Kv2.1 channels constitute an essential component of the somatodendritic delayed rectifier current (IK) in several neuronal types and regulate excitability, especially during periods of high-frequency firing.
This study outlines the identification and characterization of a novel neuronal transmembrane protein AMIGO, which contains extracellular immunoglobulin (Ig) and leucine-rich repeat (LRR) domains. AMIGO was shown to be widely expressed in cerebral neurons and localized to distinctive clusters in the neuronal plasma membrane, restricted to the cell soma and proximal part of neurites. AMIGO was further identified as an auxiliary subunit of the Kv2.1 potassium channel. AMIGO and Kv2.1 were shown to display extensive spatial and temporal colocalization and association in brain. AMIGO was also shown to modify the voltage-dependent activation of Kv2.1 and neuronal delayed rectifier current (IK).
To further understand the physiological role of AMIGO in brain, a mouse line lacking the Amigo gene was created and characterized as part of this study. Absence of AMIGO clearly reduced the amount of the Kv2.1 channel protein in mouse brain and altered the voltage-dependent activation of neuronal IK. These changes were accompanied by behavioral and pharmacological abnormalities reminiscent of those identified in schizophrenia. Concomitantly, the rare KV2.1 variant was found to be associated with human schizophrenia. These findings demonstrate the involvement of the AMIGO-Kv2.1 channel complex in schizophrenia-related behavioral domains in mice and establish KV2.1 as a susceptibility gene for schizophrenia spectrum disorders in humans.
In the current study, AMIGO was identified as an integral component of the Kv2.1 channel complex in brain. The convergent findings in humans and mice suggest a role for the AMIGO-Kv2.1 potassium channel complex in the pathophysiology of schizophrenia. Furthermore, these findings suggest AMIGO and Kv2.1 may represent potential new targets for schizophrenia treatment development.
