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.
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.
|Chang, Chia-Wei; Wilkerson, Julia R; Hale, Carly F et al. (2017) Distinct stages of synapse elimination are induced by burst firing of CA1 neurons and differentially require MEF2A/D. Elife 6:|
|Rajkovich, Kacey E; Loerwald, Kristofer W; Hale, Carly F et al. (2017) Experience-Dependent and Differential Regulation of Local and Long-Range Excitatory Neocortical Circuits by Postsynaptic Mef2c. Neuron 93:48-56|
|Loerwald, Kristofer W; Patel, Ankur B; Huber, Kimberly M et al. (2015) Postsynaptic mGluR5 promotes evoked AMPAR-mediated synaptic transmission onto neocortical layer 2/3 pyramidal neurons during development. J Neurophysiol 113:786-95|
|Gross, Christina; Raj, Nisha; Molinaro, Gemma et al. (2015) Selective role of the catalytic PI3K subunit p110? in impaired higher order cognition in fragile X syndrome. Cell Rep 11:681-8|
|Gross, Christina; Chang, Chia-Wei; Kelly, Seth M et al. (2015) Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep 11:727-36|
|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 7:1589-1600|
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 12 publications