The area CA2 of the hippocampus is a brain structure necessary for social memory, a function profoundly impaired in Alzheimer’s disease. This study led by Laure Verret (CRCA-CBI) and collaborators from Toulouse and Paris, published in iScience, shows that mice modeling Alzheimer’s disease are unable to remember a conspecific, and that this is associated with anatomical and functional abnormalities in CA2. However, a single injection of the protein NRG1 into CA2 restores social memory ability of Alzheimer’s mice.

Among the cognitive disorders in Alzheimer’s disease (AD) patients, their inability to remember others, is one of the most excruciating. However, little is known about the neural mechanisms underlying social memory. The hippocampus is a brain structure that is pivotal for memory processes, that is deeply affected in AD. In particular, the inhibitory neurons expressing the parvalbumin protein are known to be dysfunctional in the hippocampus of Alzheimer’s patients, as well as in mouse models of the disease. These neurons, often referred to as “conductors of the orchestra”, play an essential role in organizing the information flow in the brain, and thus in the emergence of complex cognitive functions, such as formation or recall of memories via the hippocampus. Within the hippocampus, the are CA2 appears crucial for the formation of social memory, specifically. This area is very rich in parvalbumin neurons and their extracellular matrix (perineuronal net, PNN). This matrix plays a protective role and ensures the maintenance of synapses on parvalbumin neurons.

In this study, the scientists observed some alterations of CA2 in AD mice that could be involved in social memory deficits. In particular, they revealed that parvalbumin neurons are less present, and that those remaining are less surrounded by PNN, in the CA2 of AD mice. This anatomical disruption is associated with a decrease of the synaptic plasticity that underlies social learning. Subsequently, the scientists conducted tests to evaluate the social behavior of AD mice. They observed that they had normal sociability, i.e., they were just as interested in their peers as healthy mice, but they were unable to remember a mouse with which they had repeatedly interacted within a few minutes ago. In order to establish a link between anatomical and functional perturbations of area CA2 and social memory deficits, the scientists then showed that a specific disruption of PNN in CA2 is sufficient to induce a alteration of social memory in healthy mice. Finally, the scientists sought to restore the presence of parvalbumin neurons and their PNN only in CA2 of AD mice. To do this, they used a protein normally present in the hippocampus during brain maturation. Surprisingly, a single injection of this protein, neuregulin-1 (NRG1), into the CA2 of Alzheimer’s mice induced in 5 days, an increase in parvalbumin neurons and their PNN. This anatomical improvement is associated with a complete recovery of the social memory ability of the AD mice, without improving other types of memory. These neural mechanisms thus revealed in a mouse model of AD could open up avenues for restoring social memory in Alzheimer’s disease.