Redesigning the hippocampus allows Alzheimer’s mice to regain the memory of others

Among the cognitive disorders in patients affected by Alzheimer’s disease, the impairment of social memory, that is, the inability to remember the people they meet or have known in the past, is without a doubt one of the most difficult to live with, both for patients and those around them. However, the neural mechanisms underlying social memory remain poorly understood. The hippocampus is a crucial cerebral structure in memory processes, and its function is severely disrupted in connection with Alzheimer’s disease. In particular, it is known that inhibitory neurons, which express the protein parvalbumin, function poorly in the hippocampus in patients with Alzheimer’s, as in mouse models of the disease; These neurons, often called “leaders”, play a key role in organizing the influx of information circulating in the brain, and therefore in the emergence of complex cognitive functions, such as creating or recalling memories via the hippocampus. Among the various subdivisions that make up the hippocampus, the CA2 area appears to be crucial for the formation of social memory in particular. However, this region is very rich in parvalbumin neurons, as well as their extracellular matrix (perineuronal net, PNN). This matrix plays a protective role and guarantees the maintenance of synapses on these neurons.

Researchers studied CA2 disorders in the hippocampus of Alzheimer’s disease model mice that may contribute to social memory deficiency. For this, observations of hippocampal sections have revealed that in CA2 of Alzheimer’s mice, the parvalbumin neurons are less present and that the remaining ones are less surrounded by PNNs compared to healthy mice. This anatomical disorder is accompanied by a decrease in synaptic plasticity that underlies social learning. Subsequently, the researchers performed tests to assess the social behavior of Alzheimer’s mice. They observed that these mice have normal sociability, that is, they are just as interested in their congeners as healthy mice, but they are unable to remember a mouse that they have nevertheless interacted with repeatedly. , every few minutes. To establish a link between the anatomical and functional disorders in the CA2 area and the social memory deficiencies, the researchers then showed that a specific disorder of the PNNs in CA2 is sufficient to induce a social memory disorder in healthy mice. Finally, the researchers only attempted to restore the presence of parvalbumin neurons and their PNN in CA2 of Alzheimer’s mice. For this, they used a protein normally present in the hippocampus during brain maturation. Surprisingly, a single injection of this protein, neuregulin-1 (NRG1), in CA2 of Alzheimer’s mice induces, only 5 days later, an increase in parvalbumin neurons and their PNNs. This anatomical improvement is accompanied by a total recovery of the social memory of Alzheimer’s mice without improving other types of memory. The neural mechanisms thus highlighted in a mouse model could open up opportunities for restoring social memory associated with Alzheimer’s disease.

© Laure Verret

Picture: The CA2 region of non-transgenic mice is rich in parvalbumin neurons, often surrounded by their extracellular matrix, the perineuronal network (PNN). This is associated with normal social memory. On the other hand, Tg2576 mice, models of Alzheimer’s disease, have a decrease in parvalbumin neurons and their PNNs in the CA2 region and an altered social memory. Injection of the neurotrophic factor neuregulin-1 (NRG1) into the CA2 region of Tg2576 mice restores the presence of parvalbumin neurons and PNNs, as well as restores the social memory capacity of these model mice of Alzheimer’s disease. Alzheimer’s.

To know more:
Altered inhibitory function in hippocampus CA2 contributes to social memory deficiency in the Alzheimer’s mouse model.
Rey CC, Robert V, Bouisset G, Loisy M, Lopez S, Cattaud V, Lejards C, Piskorowski RA, Rampon C, Chevaleyre V, Verret L.
iScience. February 24, 2022. doi: 10.1016 / j.isci.2022.103895.

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