The role of the hippocampal CA2 area in social memory
Year: 2019
Type: dissertation
Abstract: Declarative memory is a subtype of long-term memory that is expressed by a deliberate and conscious retrieval of our store of knowledge of people, places, objects and events. It is mediated through three distinct phases: memory encoding, consolidation and recall. Due to its complexity, a key approach to understand declarative memory is to study the participation of the different subregions of the hippocampal formation, an essential brain area that mediates this form of memory. Indeed, some studies have revealed specific behavioral roles of various hippocampal subregions, including dentate gyrus, CA3, CA1 and subiculum. However, little is known about the smaller and long-overlooked area CA2, even though it has a unique connectivity and distinct molecular, physiological and morphological characteristics. In mice, long-term inactivation of dorsal CA2 pyramidal neurons impaired social memory without having any impact on sociability or other forms of hippocampus-dependent memory. However, chronic CA2 silencing was recently shown to perturb the hippocampal dynamic excitatory/inhibitory balance, raising the question of whether the sociocognitive deficits found upon chronic dorsal CA2 silencing are indeed due to its direct role in this form of memory or result from indirect long-term reactive changes in brain regions outside of dorsal CA2. Moreover, long-term silencing studies could not determine if dorsal CA2 is necessary for encoding, consolidation or recall of social memory. Finally, as individual brain regions do not act in isolation, how CA2 output enables social memory remains an important question. In addition to CA2, ventral CA3 and the subset of ventral CA1 neurons that project to the nucleus accumbens medial shell, have also been implicated in social memory. However, it is unknown whether dorsal CA2, ventral CA3 and ventral CA1 are integrated into a single hippocampal circuit or if they integrate parallel circuits necessary for social memory. To explore these questions, I carried out a detailed anatomical and electrophysiological analysis of the projections from dorsal CA2 to ventral hippocampus and used pharmacogenetics and optogenetics to acutely and reversibly inactivate dorsal CA2 and its specific projections to ventral hippocampus, during the different stages of social memory. My studies show that dorsal CA2 plays an active role in social memory encoding, consolidation and recall and that it participates in social memory by providing an excitatory input to distal ventral CA1, the same ventral CA1 subregion that projects to the nucleus accumbens medial shell. In addition to its role in normal brain function, CA2 undergoes unique alterations in certain neuropsychiatric diseases associated with cognitive and social dysfunction. Postmortem studies of schizophrenic and bipolar disorder patients revealed a CA2-specific loss of inhibitory parvalbuminexpressing neurons, which was replicated in a mouse model of the 22q11.2 deletion syndrome, which represents the greatest known genetic risk factor for the development of schizophrenia. Additionally, these mice show a less excitable state of CA2 pyramidal neurons, which correlates with the upregulation of the current mediated by TREK-1 channel in CA2, a potassium channel highly expressed in CA2 and known to promote hyperpolarization. In agreement with hypofunctional CA2, presumably resulting from TKEK-1 channel upregulation, male mice of this model show impaired social memory. Therefore, to further characterize these social memory deficits and provide seminal evidence for the potential of a CA2-centered therapeutic approach, I tested both male and female mice of this 22q11.2 deletion syndrome model, in different social memory tasks and, finally, assessed the efficacy of a TREK-1 channel specific blocker in rescuing such phenotype. I found that male mutant mice have more severe social memory deficits than females and that acute systemic administration of a specific blocker of the TREK-1 channel is sufficient to rescue the social memory impairment found in female mutant mice. Altogether, my work reinforces the role of dorsal CA2 in social memory and integrates it into a hippocampal social memory circuit. Additionally, we provide evidence for a promising therapeutic approach to the socio-cognitive deficits of the 22q11.2 deletion syndrome based on the CA2 dysfunction associated with the syndrome.
Author: Torcato Meira
Language: English
Topic: Memory and Neural Mechanisms
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2953375782