Dr. Ávila-Macaya, Ariel

Protein interacting with C-kinase 1 (PICK1) is important for synaptic plasticity through directing transport of glutamate receptors and other proteins. PICK1 gene variants have been associated with schizophrenia. To examine the role of PICK1 in schizophrenia-related behaviors, mice with a mutation in the PICK1 lipid-interacting BAR domain were characterized. Male Pick1-S262T mice had disrupted AMPA receptor (AMPAR) subunit GluA1 and GluA2 protein expression in the hippocampus and prefrontal cortex (PFC). Young adult, but not juvenile (P21), Pick1-S262T mice showed decreased hippocampal synaptic transmission and deficits in long-term depression (LTD). Mutant males also had deficits in reversal learning in the Morris water maze (MWM). These observations suggest that the Pick1-S262T mutation affects AMPAR trafficking, disrupting synaptic transmission and plasticity, as well as cognitive flexibility, a core neuropsychological deficit in schizophrenia. This work suggests possible mechanisms by which a known schizophrenia susceptibility gene could contribute to clinical features of the disorder.

Neuronal calcium sensor-1 or Frequenin is a calcium sensor widely expressed in the nervous system, with roles in neurotransmission, neurite outgrowth, synaptic plasticity, learning, and motivated behaviours. Neuronal calcium sensor-1 has been implicated in neuropsychiatric disorders including autism spectrum disorder, schizophrenia, and bipolar disorder. However, the role of neuronal calcium sensor-1 in behavioural phenotypes and brain changes relevant to autism spectrum disorder have not been evaluated. We show that neuronal calcium sensor-1 deletion in the mouse leads to a mild deficit in social approach and impaired displaced object recognition without affecting social interactions, behavioural flexibility, spatial reference memory, anxiety-like behaviour, or sensorimotor gating. Morphologically, neuronal calcium sensor-1 deletion leads to increased dendritic arbour complexity in the frontal cortex. At the level of hippocampal synaptic plasticity, neuronal calcium sensor-1 deletion leads to a reduction in long-term potentiation in the dentate gyrus, but not area Cornu Ammonis 1. Metabotropic glutamate receptor-induced long-term depression was unaffected in both dentate and Cornu Ammonis 1. These studies identify roles for neuronal calcium sensor-1 in specific subregions of the brain including a phenotype relevant to neuropsychiatric disorders.