Mutations in the Ras/ERK signaling pathway cause a class of complex neurodevelopmental disorders (Rasopathies) [1] associated with cognitive impairments and autism [2]. Our mouse model studies of NS showed that dominant-active PTPN11 gene mutations (principal cause of NS) enhance Ras/ERK activation at basal levels, which then increase the basal levels of synaptic AMPA receptors; Higher basal levels of AMPA receptors occlude CA1 long-term potentiation (LTP) and consequently disrupt hippocampal-dependent learning tasks, including object/place, spatial and contextual learning & memory. Studies in NS patients and our studies in mice showed that the phenotypes of the PTPN11D61G mutation are more severe than those of the PTPN11N308D mutation, a wonderful tool to address causation in NS studies, including those proposed here. Importantly, we showed that adult treatments, with drugs that decrease Ras/ERK signaling, reverse the molecular, physiological and behavioral impairments of the NS mutant mice; Additionally, we recreated these impairments with viral vector manipulations targeted to the hippocampus (HPC) in adult mice, thus directly involving this structure and confirming that disruption of adult mechanisms contribute to the NS-associated cognitive deficits. Here, we propose integrative multidisciplinary studies with state-of-the-art approaches, such as head-mounted fluorescent miniscopes in freely moving mice and in vivo 2-photon microscopy, to address three key hypotheses: 1) Since our previous studies were focused on the hippocampal CA region, we now propose that PTPN11 NS gene mutations also affect Ras/ERK signaling, AMPA receptor function and synaptic plasticity, in another brain region key for spatial learning, the retrosplenil cortex (RSC), 2) disruptions of spatial representations in HPC and RSC, two reciprocally connected areas critical for spatial processing, contribute to the spatial learning and memory impairments in NS mutant mice, and 3) RSC-dependent molecular, cellular, and behavioral deficits, as well as circuit deficits in RSC and HPC, can be reversed in adult NS mutants by an FDA approved drug (lovastatin) that we demonstrated reverses the NS-associated molecular, cellular and behavioral deficits in HPC. Beyond elucidating molecular, cellular and circuit mechanisms responsible for the spatial learning deficits associated with Rasopathies, which we hope will lead to treatments, the studies proposed here will also further our knowledge of the functional significance and interdependence of spatial representations in HPC and RSC, and they will be critical to understand other behavioral phenotypes associated with Rasopathies such as autism.

Public Health Relevance

The public health relevance of the proposed research is three-fold: (1) To elucidate molecular, cellular and circuit mechanisms responsible for the cognitive deficits associated with Rasopathies, including Noonan Syndrome, a condition that affects one in 2000 people world-wide; (2) To test potential treatments, including an FDA approved drug that could be immediately used in clinical trials. (3) To test the functional significance and interdependence of spatial representations in hippocampus and retrosplenial cortex. Insights into spatial representations may lead to better treatments for spatial cognitive deficits common in a number of disorders from Alzheimer's to intellectual disabilities.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Buhring, Bettina D
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University of California Los Angeles
Schools of Medicine
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