What Is the Potential Relevance of Hippocampal Area CA2 in Neurologic Disorders?

The hippocampus has a critical role in the online processing of information; encoding, storage, and retrieval of episodic memory; and novelty detection. These functions have been classically associated with a trisynaptic circuit connecting the entorhinal cortex, the dentate gyrus, area CA3, and area CA1. Until recently, the role of area CA2, located between CA3 and CA1, has been underappreciated. However, increased evidence indicates that, despite its small size,¹ area CA2 has a critical role in in regulating activity throughout the hippocampal circuit and has a unique importance in social recognition memory.^2-8 Area CA2 has widespread connectivity with other hippocampal regions² and has unique structural features, electrophysiologic responses, pattens of receptor expression, and subcortical inputs. Pyramidal CA2 neurons are more resistant to excitotoxicity than those in other hippocampal subfields.⁹ However, area CA2 is susceptible to accumulation of alpha-synuclein^10,11 and tau.¹² Experimental studies show loss or impaired function of a critical subpopulation of local inhibitory CA2 interneurons in several disorders, including temporal lobe epilepsy,¹³ Alzheimer disease (AD), multiple sclerosis, schizophrenia, and autism spectrum disorder.¹⁴.