Neuronal network dynamics in a social memory circuit in normal versus autistic conditions

Abnormal excitation/inhibition balance and hippocampal network activity contribute to Autism Spectrum Disorders (ASD), which affect social interactions and memory. Recent studies show that a central circuit for the control of these behaviors includes dorsal CA2 and ventral CA1 in the hippocampus. Using recently generated Inscopix microendoscopes it was shown that a wild type mouse has more ventral CA1 excitatory projection neurons (PNs) responding to interaction with a familiar than with a foreign mouse. However, the contribution of other cell types and in particular of inhibitory interneurons (iNs) to ventral CA1 activity during social interactions has not been addressed.
In collaboration with clinicians, the team has recently identified the NeuroD2 gene, which encodes a bHLH transcription factor, as a new ASD gene. Then we found that NeuroD2 KO mice have deficits in social interactions and memory (unpublished). In the hippocampus, NeuroD2 is confined to PNs, which become hyper-excitable in NeuroD2 KO mice. Our first objective is to determine whether and how network dynamics in dorsal CA2 and ventral CA1 are altered in NeuroD2 KO mice in control or social contexts, by imaging PN and iN activity with our newly acquired last generation Inscopix microendoscopes (Fig. 1, financed by a FRC grant).
Furthermore, the de Chevigny team has found that parvalbumin (PV)-expressing iNs express much lower levels of PV in NeuroD2 KO mice, which in light of recent studies suggests that the parvalbumin network is hypoactive in these mutants. This result is reminiscent of recent studies indicating hyopactivity of PV+ iNs in neuropsychiatric conditions and suggests that a low activity of PV iNs might be a common outcome of different insults that causally alter hippocampus-dependent social behavior. Interestingly, PV cells have been shown to contribute to the spatio-temporal patterning of CA1 assemblies, further supporting the hypothesis that these neurons may be disturbed in NeuroD2 KO. In this context, our second objective is to optogenetically stimulate PV iNs in NeuroD2 KO mice and seek for restoration of network activity and social memory, and conversely to inhibit PV iNs in wild type mice to seek for alterations in network activity (assembly arrangement) and social behavior.
We seek for a talented student interested in in vivo calcium imaging in freely moving mice. The student will take advantage of our last generation nVoke Inscopix microendoscope that allows optigenetic stimulations of PV iNs. She/he will record hippocampal activity in selected cell populations in WT vs KO mice, in vCA1 or dCA2, during a social discrimination task. She/he will then participate in the analyses of the calcium imaging movies using custom-made and freely available Matlab codes.

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