Perineuronal nets, hippocampal plasticity, and autism spectrum disorder. - Project Summary Autism Spectrum Disorder (ASD) is a heterogeneous group of neurodevelopmental conditions, which often present with social recognition dysfunction. Phelan-McDermid syndrome and Fragile X syndrome, two monogenic causes of ASD, have social recognition deficits, such as difficulty recognizing familiar faces, emotions on faces, and familiar voices. Transgenic mouse models based on genes known to be mutated in Phelan- McDermid (SHANK3) and Fragile X (FMR1) display deficits in social recognition during development as well as in adulthood. The CA2 region of the hippocampus has been identified as a key brain region in social recognition function both during development and in adulthood. Both Shank3B and Fmr1 KO mice have atypical perineuronal nets (PNNs), extracellular matrix structures known to regulate plasticity, in the CA2 region of the developing hippocampus. Normalizing CA2 PNNs in Shank3B and Fmr1 KO mice can restore social recognition function, and some evidence suggests that PNN correction may be most effective if it occurs during a sensitive period of development. In other systems, PNNs play a role in connectivity development by sequestering molecules like semaphorin-3A (sema3A), which is known to provide guidance cues to axons and to inhibit synapse elimination. The supramammillary nucleus (SuM) of the hypothalamus projects to the CA2 region, a circuit that is known to contribute to social novelty detection and social discrimination in adulthood. In the CA2 region, SuM axons release substance P (SP), a neuropeptide known to enhance neuronal activity. SuM afferents, as well as SP receptors, are abnormal in the CA2 of Shank3B and Fmr1 KO mice although it remains unknown whether SP signaling contributes to social recognition. The broad, long-term objectives of this proposal are to investigate potential roles for PNNs and sema3A in the development of SuM-CA2 structure and function in healthy, as well as Shank3B and Fmr1 KO mice. More specifically, we will use pharmacological and viral manipulations of PNNs, sema3A, and SP signaling, chemogenetic manipulations of neuronal activity, lipophilic dye and immunolabeling for dendritic spines, synaptic markers, and immediate early gene expression, in vivo electrophysiology, and behavioral analyses in wildtype mice and transgenic mice with social dysfunction. These approaches will be used to probe potential mechanisms of healthy CA2 development, and to test targets of intervention for correcting function both during development and in adulthood. Taken together, the findings of the proposed experiments will advance our understanding of how PNNs and sema3A affect SuM- CA2 structure and function during development, and whether SP signaling can be harnessed to restore CA2 function in adulthood in genetic mouse models for ASD.
