CORTICAL CIRCUIT CHANGES AND MECHANISMS IN A MOUSE MODEL OF FRAGILE X SYNDROME
Jay Robert Gibson
University Of Texas Sw Med Ctr/dallas, Dallas, Tx 75390-9105
Grant 5R01HD056370-02 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: 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
Keywords: 12-20 years old; Accounting; Acute; Adolescence; Age; Allergy; Animal Model; Animal Models and Related Studies; Area; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Behavior; Behavioral; Brain; Causality; Cells; Cognition; Cognition Disorders; Cognitive; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive deficits; Cognitive function abnormal; Data; Dendritic Spines; Development; Disease; Disorder; Disturbance in cognition; Drugs; Encephalon; Encephalons; Equilibrium; Escalante syndrome; Etiology; FMR-1 Protein; FMR1; FMR1 Gene; FMR1 Protein; FMR1 protein, fragile X; FMRP protein; Feedback; Fmr1 gene, ; Fmr1, ; Fragile X; Fragile X Mental Retardation 1 Gene; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetic; Genetic Alteration; Genetic Change; Genetic defect; Hereditary; Human; Human, General; Hypersensitivity; Impaired cognition; Impairment; In Vitro; Inherited; Kanner`s Syndrome; Knockout Mice; Knowledge; Lead; Link; Mammals, Mice; Man (Taxonomy); Man, Modern; Martin-Bell Syndrome; Martin-Bell-Renpenning syndrome; Measures; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Medication; Membrane; Mental Retardation; Metabotropic Glutamate Receptors; Methods; Mice; Mice, Knock-out; Mice, Knockout; Murine; Mus; Mutation; Neocortex; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurobiology; Neurocyte; Neurologic; Neurological; Neurons; Null Mouse; Patients; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Preparation; Prevalence; Proteins; Receptors, Metabotropic Glutamate; Renpenning syndrome 2; Role; Sensory; Slice; Spinal Column; Spine; Structure; Synapses; Synaptic; Synaptic Membranes; Synaptic plasticity; Syndrome; Testing; Vertebral column; X-linked mental deficiency-megalotestes syndrome; X-linked mental retardation with fragile X syndrome; X-linked mental retardation-fragile site 1 syndrome; adolescence (12-20); autism spectrum disorder; autism-fragile X (AFRAX) syndrome; autism-fragile X syndrome; backbone; balance; balance function; cell type; cellular targeting; cognitive change; cognitive disease; cognitive disorder; cognitive dysfunction; cognitive loss; cognitively impaired; dendrite spine; disability; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; drug/agent; effective therapy; excitatory neuron; experiment; experimental research; experimental study; extracellular; fra(X) syndrome; fra(X)(28) syndrome; fra(X)(q27) syndrome; fra(X)(q27-28) syndrome; fragile X mental retardation 1; fragile X mental retardation-1 protein; fragile X-mental retardation syndrome; fragile Xq syndrome; fragile site mental retardation 1; fragile x [{C0016667}]; fragile x syndromes; gene product; genome mutation; heavy metal Pb; heavy metal lead; homotypical cortex; inhibitory neuron; intervention development; isocortex; long term memory; loss of function mutation; macro-orchidism-marker X (MOMX) syndrome; macro-orchidism-marker X syndrome; mar(X) syndrome; marker X syndrome; membrane structure; mental retardation-macroorchidism syndrome; model organism; mouse model; neocortical; neopallium; neural circuit; neural circuitry; neurobiological; neurobiological mechanism; neuronal; perceptual stimulus; physicochemical phenomena related to the senses; postsynaptic; presynaptic; public health relevance; research study; sensory stimulus; social role; synapse function; synaptic function; teenage; therapeutic target; therapy development; treatment development
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
Project start date: 2009-04-09
Project end date: 2013-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: PA-07-284
5R01HD056370-02 (2010): $290266
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Jay Robert Gibson
Cortical Circuit Changes And Mechanisms In A Mouse Model Of Fragile X Syndrome
Jay Robert Gibson
Neuroscienceuniversity Of Texas Sw Med Ctr/dallas
Grant 1R01HD056370-01A2 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development IRG: DBD
Abstract: 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
Project start date: 2009-04-09
Project end date: 2013-02-28
3R01HD056370-01A2S1 (2009): $47848