Mechanisms for Neurological Dysfunction in NF1 and Noonan Syndrome

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): Neurofibromatosis Type I (NF1) and Noonan syndrome (NS), two related disorders with mental health phenotypes, are associated with cognitive deficits in nearly 1 in 2000 people worldwide. Compelling molecular and cognitive parallels between NF1 and NS suggest that their learning problems are caused by a common mechanism. Previous studies in our lab suggested the following mechanistic hypothesis for their cognitive deficits, that we propose to test here: 1) The NS and NF1 gene products regulate the activation of Ras/MAPK/ synapsin I signaling in hippocampal inhibitory terminals; 2) This signaling pathway modulates GABA release; 3) During learning NS and NF1 mutations result in the over activation of this signaling pathway, abnormally high increases in inhibition, disruptions in the activation of principal neurons, and deficits in the induction of long-term potentiation (LTP). Our specific aims are: 1. To test the hypotheses that learning triggers SHP-2/neurofibromin/Ras/MAPK-dependent increases in GABA-release, and that the NF1 and NS mouse mutations inappropriately increase these inhibition enhancements and therefore disrupt learning. This aim will focus on how learning changes inhibition. 2. To test the hypothesis that increased inhibition in Nf1 mice (and potentially NS mutants) prevents the activation of principal neurons in the hippocampus during learning, and consequently causes deficits in hippocampal-dependent learning. We propose to use transgenic fluorophores that track neuronal activity, as well as a novel two-photon imaging technique Micro Optic Probes (MOPs), to track longitudinally the activation patterns of hippocampal CA1 neurons during training in a spatial learning task. 3. To test the hypothesis that SHP-2 activating mutations in mouse hippocampal inhibitory neurons lead to Ras/MAPK/synapsin I-dependent increases in GABA release in the CA1 region, CA1 LTP deficits and hippocampal-dependent learning impairments. To test this hypothesis, we will use mouse mutants we already have and two inducible mutants that will restrict a SHP-2D61G NS mutation to either adult excitatory or inhibitory neurons. We will also use pharmacological inhibitors that target the mechanisms tested, including a FDA-approved drug. We will determine whether these drugs reverse the biochemical, physiological and behavioral deficits in animal models of NS. One of these pharmacological inhibitors (lovastatin), currently being tested in NF1 clinical trials, could also eventually be tested in NS clinical trials.