2013 Theses Doctoral

Genetically targeted anatomical and behavioral characterization of the cornu ammonis 2 (CA2) subfield of the mouse hippocampus

Hitti, Frederick Luke

The hippocampus is critical for storing declarative memory, our repository of knowledge of who, what, where, and when. Mnemonic information is processed and encoded in the hippocampus through several parallel routes, most notably the trisynaptic pathway, in which information proceeds from entorhinal cortex (EC) to dentate gyrus (DG) to CA3 and then to CA1, the main hippocampal output. Absent from this pathway is the CA2 subfield, a relatively small area interposed between CA3 and CA1 that has recently been shown to mediate a powerful disynaptic circuit linking EC input with CA1 output. Usually ignored or grouped together with CA3, CA2 has generally escaped exploration presumably due to its relatively small size and somewhat ill-defined borders. A few studies have proposed an important role for the CA2 subfield of the hippocampus, however, the relevance of this subfield in a behaving animal has not been explored. The function of a particular brain region may be inferred by examining the effects of a lesion of that area. Indeed, the hippocampus's role in learning and memory was elucidated following the bilateral medial temporal lobe ablation of Henry Molaison (patient H.M.). Similarly, a lesion of CA2 could be used to infer its role in learning, memory, and disease. Due to the relatively small size of CA2, physical or chemical lesions are not precise enough to ablate this region without collateral damage. To overcome this limitation, I generated a CA2-specific transgenic mouse line to enable genetic targeting of this subfield. I used this mouse line to map CA2 connectivity and explore its behavioral role. Using monosynaptic rabies tracing, CA2 axon tracing, and electrophysiology, I confirmed the disynaptic pathway and presence of septal and subcortical inputs to CA2. Genetically targeted inactivation of CA2 caused a remarkably profound loss of social memory, with no change in sociability. This impairment was not the result of a general loss of hippocampal function as CA2-inactivation did not impact performance on several other hippocampal-dependent tasks, including spatial and contextual memory. These behavioral and anatomical results thus reveal CA2 as a hub of sociocognitive processing and implicate its dysfunction in social endophenotypes of psychiatric diseases such as schizophrenia and autism.