The synthesis of proteins in synapto-dendritic domains is tightly regulated but in fragile X mental retardation (FXS) and related cases of autism, translation at dendrites is dysregulated due to the loss of at least one regulatory mechanism, the fragile X mental retardation protein (FMRP). How this dysregulation of translation contributes to the clinical expression of impaired cognition in FXS and autism is unknown. An important clue and departure point for formulating our central hypothesis is the fact that loss of FMRP promotes hyperexcitability of neural circuits through overstimulation of group I metabotropic glutamate receptors (mGluR). Group I mGluR-dependent responses increase neuronal excitability and are a necessary determinant of the gamma band (30-100 Hz) electrical oscillations that coordinate action potential discharge throughout the vast networks of excitatory and inhibitory neurons that is the substrate for cognition. Our central """"""""discoordination"""""""" hypothesis is that dysregulated translation causes cognitive impairments in FXS and autism because dysregulated translation leads to exaggerated group I mGluR responses that produce inappropriately coordinated synchronization and desynchronization of the electrical activity in the networks of neurons that mediate cognitive information processing in the mammalian brain. This hypothesis is based on advances in the basic science of cognition and the recognition that abnormal neural synchrony is emerging as the core pathophysiology underlying cognitive impairments in mental disorders, including schizophrenia, depression, FXS, and autism. We propose to characterize neural synchrony and cognition in five mutant mouse models of dysregulated RNA translation. In three Specific Aims, we examine neural synchrony in mice lacking the FMRP gene Fmr1, mice lacking BC1 RNA, a second repressor of translation in the brain, and mice lacking both FMRP and BC1 RNA. To confirm that abnormalities arise from acute loss of translation repressors (as predicted by the discoordination hypothesis) and not due to developmental effects, we will use a conditional Fmr1 knockout mutant mouse model that has lost FMRP only in adulthood as well as an inducible knock-in Fmr1 mutant mouse model in which Fmr1 is restored in adulthood under experimental control. First, we investigate abnormalities in the cortical EEG of the mice and determine the dependence on group I mGluR, M1 and 5-HT2 signaling. Second, we investigate neural coordination abnormalities in hippocampus and their synapse-specific origins using linear arrays of electrodes and pharmacological manipulations. Third, we identify which abnormalities coincide with cognitive impairments in the mutant mice. It is our overall goal to determine how translational dysregulation contributes to associated abnormalities in neural synchrony and cognition in fragile X mental retardation and autism.

Public Health Relevance

This project aims to understand how loss of translational regulation contributes to cognitive impairments as seen in fragile X mental retardation and autism. We will determine whether dysregulation of translation in neurons contributes to impaired cognitive control of behavior by group I metabotropic receptor overstimulation that promotes discoordinated synchronization of electrical neural network activity in the mammalian brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH099128-01
Application #
8418970
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Osborn, Bettina D
Project Start
2012-12-18
Project End
2017-11-30
Budget Start
2012-12-18
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$375,588
Indirect Cost
$125,588
Name
New York University
Department
Neurology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
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Talbot, Zoe Nicole; Sparks, Fraser Todd; Dvorak, Dino et al. (2018) Normal CA1 Place Fields but Discoordinated Network Discharge in a Fmr1-Null Mouse Model of Fragile X Syndrome. Neuron 97:684-697.e4
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Tsokas, Panayiotis; Hsieh, Changchi; Yao, Yudong et al. (2016) Compensation for PKM? in long-term potentiation and spatial long-term memory in mutant mice. Elife 5:
Radwan, Basma; Dvorak, Dino; Fenton, André A (2016) Impaired cognitive discrimination and discoordination of coupled theta-gamma oscillations in Fmr1 knockout mice. Neurobiol Dis 88:125-38

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