Autism spectrum disorders (ASDs) and related neuropsychiatric diseases, such as schizophrenia, are thought to involve alterations in neural circuitry in different brain regions, including the hippocampus, an area critical for memory formation. Most studies on the role of the hippocampus in learning and memory have focused on information flow through the hippocampal CA3, CA1 and dentate gyrus subregions. Much less is known about the hippocampal CA2 region, a relatively small area that is altered in individuals with schizophrenia and bipolar disorder. The CA2 region is of particular interest in ASD because it has high levels of receptors for the social hormones oxytocin and vasopressin, which have been implicated in ASD.
Steven Siegelbaum and his colleagues at Columbia University recently developed a genetically engineered mouse line that enables the selective manipulation and labeling of CA2 neurons1. Using this mouse, Siegelbaum and his team were able to examine the role of CA2 in hippocampal-dependent memory by specifically silencing the CA2 neurons. Surprisingly, CA2 silencing had little effect on many forms of hippocampal-dependent learning and memory. However, loss of CA2 function completely abolished social memory.
To examine the potential role of CA2 in disease, the team recently studied a genetic mouse model of the human 22q11.2 deletion syndrome, which is closely linked to schizophrenia and autism. Their preliminary data suggest that this mouse mutant has both altered CA2 circuitry and deficits in social memory.
In the current project, Siegelbaum and his colleagues propose to examine whether altered CA2 function is generally observed in ASD by examining three prominent genetic models of ASD (ie., mice homozygous for deletion of CNTNAP2, SHANK 3 and NRXN1a). If altered CA2 function is observed, the researchers will then attempt to rescue CA2 function by genetic manipulations of membrane excitability or synaptic transmission. Future experiments would then test whether rescue of CA2 function also rescues the deficits in social memory observed in these ASD mouse lines. If successful, these experiments will help identify new targets for the development of pharmacological agents that may be useful for treating altered social behavior associated with ASD and other neuropsychiatric disorders.
References:
1. Hitti F.L. and S.A. Siegelbaum Nature 508, 88-92 (2014) PubMed
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
