Akt1 deficiency in schizophrenia and impairment of hippocampal plasticity and function

Abstract

Genetic studies have associated deficient function of the serine/threonine kinase Akt1 with schizophrenia. This disorder is associated with developmental, structural, and functional abnormalities of the hippocampus that could be traced to abnormal Akt1 function. To establish a closer connection between Akt1 and hippocampal function, mice with a selective deletion of Akt1 (Akt1(-/-) mice) were examined for physiological and behavioral outcomes dependent on the hippocampus and associated with schizophrenia. Genetic deletion of Akt1 was associated with both impaired proliferative capacity of adult-born hippocampal progenitors and hippocampal long-term potentiation, indicating deficient functions of this brain region associated with neuroplasticity. Moreover, Akt1(-/-) mice demonstrated impairments in contextual fear conditioning and recall of spatial learning, behaviors known to selectively involve the hippocampus. Akt1(-/-) mice also showed reduced prepulse inhibition of the acoustic startle response, a sensorimotor gating response that is perturbed in schizophrenia. Postmortem tissue samples from patients with schizophrenia showed significant reductions of phosphorylated Akt levels in hilar neurons of the dentate gyrus, the neurogenic zone of the hippocampus. Taken together, these results implicate the Akt1 isoform in regulating hippocampal neuroplasticity and cognition and in contributing to the etiology of schizophrenia.