Abstract
Glutamatergic dysfunction is strongly implicated in schizophrenia and mood disorders. GluA1 knockout (KO) mice display schizophrenia- and depression-related abnormalities. Here, we asked whether GluA1 KO show mania-related abnormalities. KO were tested for behavior in approach/avoid conflict tests, responses to repeated forced swim exposure, and locomotor responses under stress and after psychostimulant treatment. The effects of rapid dopamine depletion and treatment with lithium or a GSK-3β inhibitor (SB216763) on KO locomotor hyperactivity were tested. Results showed that KO exhibited novelty- and stress-induced locomotor hyperactivity, reduced forced swim immobility and alterations in approach/avoid conflict tests. Psychostimulant treatment and dopamine depletion exacerbated KO locomotor hyperactivity. Lithium, but not SB216763, treatment normalized KO anxiety-related behavior and partially reversed hyperlocomotor behavior, and also reversed elevated prefrontal cortex levels of phospho-MARCKS and phospho-neuromodulin. Collectively, these findings demonstrate mania-related abnormalities in GluA1 KO and, combined with previous findings, suggest this mutant may provide a novel model of features of schizoaffective disorder.
Highlights
Genes and molecules involved in excitatory synapse function are attractive candidates as risk factors for psychiatric conditions with a broad clinical phenotype such as schizoaffective disorder
To identify molecular mechanisms associated with the GluA1 KO phenotype and its predicted rescue by lithium, we evaluated the activity of two markers (MARCKS and neuromodulin) of protein kinase C (PKC), an intracellular pathway implicated in mania (Szabo et al, 2009)
The goal of the current study was to test whether mutant mice lacking GluA1 AMPAR subunit exhibit ‘mania-related’ phenotypic abnormalities
Summary
Genes and molecules involved in excitatory synapse function are attractive candidates as risk factors for psychiatric conditions with a broad clinical phenotype such as schizoaffective disorder. Such ‘synaptologies’ have been posited to underlie neurodevelopmental disorders such as autism (Sudhof, 2008) but could contribute to the pathophysiology of neuropsychiatric disorders with a major developmental component such as schizoaffective disorder. In this context, L-glutamate is the major excitatory neurotransmitter system in the central nervous system and a key regulator of synaptic function and plasticity (Malenka and Bear, 2004). There are reports of reduced GluA1 gene expression in the post-mortem brains of persons with bipolar disorder (Beneyto et al, 2007)
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