Dysregulation of Protein Synthesis in Fragile X Syndrome and Other Developmental Disorders

National Institute Of Mental Health

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Abstract

The protocol involved in this project is 06-M-0214, NCT00362843. During the 2017 funding period, we addressed the following: 1) rCPS measured with the L-1-C-11leucine PET method in patients with FXS and healthy volunteers studied either under dexmedetomidine sedation or in the awake state, 2) Effects of treatment with metformin on rCPS and behavior in Fmr1 KO mice, 3) Effects of treatment with an inhibitor of phosphodiesterase-4D (PDE-4D) on behavior and rCPS in Fmr1 KO mice, 4) rCPS in Tsc2+/- mice, 5) Sleep abnormalities in Fmr1 KO and Tsc2+/- mice. 1) Fragile X syndrome. We continue to analyze results of our studies of rCPS in patients with FXS measured with the L-1-C-11leucine PET. In studies of patients and healthy controls studied under sedation we did not find increased rCPS in the patient population. As with our previous studies of FXS subjects under propofol sedation, rCPS in dexmedetomidine-sedated subjects are lower compared with age-matched controls. Currently, we are focusing on studies of awake patients and healthy controls studied with a modified protocol. Our hypothesis is that rCPS is altered in patients with FXS compared with age-matched controls. These studies are ongoing. 2) Metformin treatment of Fmr1 KO mice. T. Jongens (University of Pennsylvania) reported recently that elevated insulin signaling is involved in the expression of behavioral phenotypes in the Drosophila model of FXS (dfmr1). We are following up this finding by testing the efficacy of metformin on rCPS and behavior in Fmr1 KO mice. Metformin is a biguanide drug used in the treatment of type 2 diabetes. Mice are treated chronically as adults and tested on tests of memory and rCPS are measured. The results of these studies are being analyzed. 3) Treatment of Fmr1 KO mice with an inhibitor of PDE-4D. Work from Berry-Kravis (Rush College of Medicine) indicates that cAMP is reduced in peripheral cells from patients with FXS and that in neuroblastoma cells cAMP production is regulated by FMRP. Moreover, work from the laboratory of T. Jongens shows that inhibition of PDE-4 ameliorates memory deficits in the dfmr1 fly and restores mGluR-dependent LTD to WT levels in the Fmr1 KO mouse. In collaboration with Tetra Discovery Partners, we are testing the efficacy of a negative allosteric modulator (NAM) of PDE-4D (BPN-14770). We are chronically treating Fmr1 KO mice with the PDE-4D NAM and measuring its effects on behavior and rCPS. These studies are ongoing. 4) Another syndromic form of autism under study in the SNPM is tuberous sclerosis complex (TSC). TSC is an autosomal dominant neurogenetic disorder manifested by a high incidence of seizures, intellectual disability, and autism. TSC is caused by mutations in either TSC1 or TSC2, which encode for proteins that form a complex and interact with a small GTP-binding protein, RHEB, to inhibit mTORC1. mTORC1 is a central regulator of ribosomal biogenesis and translation initiation, and loss of TSC1/2 function results in increased activity of mTORC1. We hypothesized that haploinsufficiency of TSC2 (Tsc2+/-) in mice would lead to increased rCPS. To date, our in vivo measurements of rCPS in freely-moving awake, adult, male Tsc2+/- mice indicate that rCPS is decreased in selective brain regions. Current experiments are addressing the effects of the mutation in TSC2 on recycling of leucine derived from protein degradation in the tissue; this is a critical factor in the equation for rCPS. These studies are ongoing. 5) Sleep and neurodevelopmental disorders. Sleep abnormalities are one of the most prevalent concurrent disorders in patients diagnosed with neurodevelopmental syndromes. In these patients, the severity of behavioral abnormalities and the severity of sleep abnormalities are correlated. Given the importance of sleep in developmental plasticity, we sought to examine sleep behavior in two animal models of single gene neurodevelopmental disorders, FXS and TSC. We used home cage monitoring to investigate total sleep times during the light and dark phases. We found that Fmr1 KO mice at two and six months of age sleep less than WT mice in the light phase. In younger animals (at p21), we found no difference between Fmr1 KO and WT mice in sleep times. Sleep deficits were not restored by treatment with a GABA-B agonist, R-baclofen. The results of these studies are in press (Frontiers in Molecular Neuroscience) Future studies will address the ability of other drugs to improve sleep and improve behavioral phenotypes. Future studies will also address sleep in other single gene neurodevelopmental disorders.