Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and is caused by loss of function mutations in the Fragile X Mental Retardation gene (FMR1). It results in debilitating behavioral and cognitive impairments, and to date, there are no effective treatments. Because up to 30% of FXS patients are also autistic, understanding the etiology of FXS may also help us understand Autism Spectrum Disorder (ASD). Patients with FXS, as well as other forms of mental retardation, have abnormal dendritic spines, suggesting that abnormal synaptic function contributes to the cognitive deficits of this disease. In the FXS mouse model, the Fmr1 knockout mouse (Fmr1 KO), there is altered synaptic plasticity suggesting a possible cellular mechanism for the cognitive deficits. However, the final alterations in baseline synaptic function, network connectivity, and network function have remained allusive. Because neocortex is widely hypothesized to be critical to cognition, it is reasonable to hypothesize that synaptic and network function changes in this structure may directly underlie the cognitive deficits in FXS and autism. Accordingly, we have found clear, profound changes in the Fmr1 KO mouse at 3 levels of neurobiological function in the neocortex - synaptic, cellular, and network. Most saliently, excitatory drive is decreased 2-fold onto one class of inhibitory neuron and the excitability of excitatory neurons is increased. Together these changes suggest that neocortical circuitry is hyperexcitable. This is confirmed by changes in network function observed in vitro. These changes are consistent with the hypothesis that the balance of excitation and inhibition is altered in mental retardation and autism. Utilizing electrophysiological methods in acute brain slice preparations, we propose the following specific aims: 1) determine where and when in the neocortex functional changes exist, 2) determine the mechanisms underlying synaptic and cellular changes, and 3) determine the cellular underpinnings and mechanisms of network function change. Our results will help us understand the neurobiological mechanisms underlying FXS and autism and could lead to the development of treatments to reverse these syndromes in humans.

Public Health Relevance

We have found alterations in neocortical circuitry in the mouse model of Fragile X Syndrome - the Fmr1 KO mouse. These alterations include synaptic and network function, and they indicate that neocortical networks are hyperexcitable. Accordingly, these changes could underlie the increased sensitivity to sensory stimuli or even cognitive disabilities in Fragile X Syndrome patients. Our proposed line of study investigating these alterations will provide potential cellular targets for genetic and drug treatments for both Fragile X Syndrome and autism since both disorders often occur together.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Urv, Tiina K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
Zip Code
Wilkerson, Julia R; Tsai, Nien-Pei; Maksimova, Marina A et al. (2014) A role for dendritic mGluR5-mediated local translation of Arc/Arg3.1 in MEF2-dependent synapse elimination. Cell Rep 7:1589-600
Patel, Ankur B; Loerwald, Kristofer W; Huber, Kimberly M et al. (2014) Postsynaptic FMRP promotes the pruning of cell-to-cell connections among pyramidal neurons in the L5A neocortical network. J Neurosci 34:3413-8
Patel, Ankur B; Hays, Seth A; Bureau, Ingrid et al. (2013) A target cell-specific role for presynaptic Fmr1 in regulating glutamate release onto neocortical fast-spiking inhibitory neurons. J Neurosci 33:2593-604
Jakkamsetti, Vikram; Tsai, Nien-Pei; Gross, Christina et al. (2013) Experience-induced Arc/Arg3.1 primes CA1 pyramidal neurons for metabotropic glutamate receptor-dependent long-term synaptic depression. Neuron 80:72-9
Ronesi, Jennifer A; Collins, Katie A; Hays, Seth A et al. (2012) Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci 15:431-40, S1
Hays, Seth A; Huber, Kimberly M; Gibson, Jay R (2011) Altered neocortical rhythmic activity states in Fmr1 KO mice are due to enhanced mGluR5 signaling and involve changes in excitatory circuitry. J Neurosci 31:14223-34
Gibson, Jay R; Huber, Kimberly M; Sudhof, Thomas C (2009) Neuroligin-2 deletion selectively decreases inhibitory synaptic transmission originating from fast-spiking but not from somatostatin-positive interneurons. J Neurosci 29:13883-97