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.