Sensory hypersensitivity and abnormal sensory processing contribute significantly to behavioral problems associated with Fragile X Syndrome (FXS). Sensory hypersensitivity and audiogenic seizures in the FXS mouse model, Fmr1 knockout (KO) mice, suggest a hyperexcitability of sensory circuits. We have discovered a robust hyperexcitability, as well as changes in specific excitatory and inhibitory synaptic connections, in neocortical circuits in the Fmr1 KO mice. Our work has also revealed a novel molecular mechanism underlying hyperexcitability - impaired scaffolding among Homer proteins and resulting enhanced metabotropic glutamate receptor (mGluR5) signaling. We hypothesize that, in addition to enhancing mGluR5 function, impaired Homer scaffolding causes a displacement of the endocannabinoid (eCB) synaptic signaling resulting in differentially altered eCB-dependent plasticity of excitatory and inhibitory synapses in the Fmr1 KO. Evidence also indicates that ERK activity is involved in this altered plasticity. New data find that increased CamKlla phosphorylation of Homer causes the loss of scaffolding. As part of the FXS center, we propose to examine the role that these biochemical mechanisms and 3 synaptic pathways play in hyperexcitability of the auditory cortex in the Fmr1 KO mouse. Coordination of experiments are planned to link the alterations we find in the auditory neocortex with deficits in auditory sensory processing in Fmr1 KO mice (P2) and FXS patients (P3). In, Aim 1, we examine the developmental and circuit mechanisms underlying circuit hyperexcitability. Based on existing candidate targets for potential FXS treatment, we also examine the acute effects of clinically-approved, potential therapeutics on neocortical hyperexcitability.
In Aim 2, we determine if mGluR5-eCB synaptic plasticity is dysregulated at 3 different neocortical synaptic pathways with known changes in the Fmr1 KO that could underlie hyperexcitability.
In Aim 3, we determine if enhanced CaMKlla phosphorylation of Homer causes circuit hyperexcitibility and dysregulated mGluR5-eCB plasticity of specific synaptic circuits.
In Aim 4, and in collaboration with P2, we examine the role of altered matrix-metalloproteinase (MMP9) signaling in hyperexcitability and disrupted Homer scaffolds

Public Health Relevance

Most Fragile X Syndrome (FXS) patients display hypersensitivity to sensory stimuli which is a major cause of behavioral problems. Our study of hyperexcitable circuits in the auditory cortex of the FXS model mouse will help determine the underlying circuit and biochemical mechanisms underlying sensory hypersensitivity. Our findings will be used for designing treatment strategies for FXS.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54HD082008-01
Application #
8794679
Study Section
Special Emphasis Panel (ZHD1-DSR-Y (53))
Project Start
Project End
Budget Start
2014-09-22
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$538,277
Indirect Cost
$187,018
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Ethridge, L E; White, S P; Mosconi, M W et al. (2016) Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome. Transl Psychiatry 6:e787
Lovelace, Jonathan W; Wen, Teresa H; Reinhard, Sarah et al. (2016) Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome. Neurobiol Dis 89:126-35
Ouyang, Minhui; Cheng, Hua; Mishra, Virendra et al. (2016) Atypical age-dependent effects of autism on white matter microstructure in children of 2-7 years. Hum Brain Mapp 37:819-32
Takarae, Yukari; Sablich, Savanna R; White, Stormi P et al. (2016) Neurophysiological hyperresponsivity to sensory input in autism spectrum disorders. J Neurodev Disord 8:29
Mosconi, Matthew W; Mohanty, Suman; Greene, Rachel K et al. (2015) Feedforward and feedback motor control abnormalities implicate cerebellar dysfunctions in autism spectrum disorder. J Neurosci 35:2015-25
Guo, Weirui; Ceolin, Laura; Collins, Katie A et al. (2015) Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model. Cell Rep 13:2297-311
Miller, Haylie L; Ragozzino, Michael E; Cook, Edwin H et al. (2015) Cognitive set shifting deficits and their relationship to repetitive behaviors in autism spectrum disorder. J Autism Dev Disord 45:805-15
Najjar, Fedra; Owley, Thomas; Mosconi, Matthew W et al. (2015) Pharmacogenetic Study of Serotonin Transporter and 5HT2A Genotypes in Autism. J Child Adolesc Psychopharmacol 25:467-74
Mosconi, Matthew W; Wang, Zheng; Schmitt, Lauren M et al. (2015) The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders. Front Neurosci 9:296
Amodeo, Dionisio A; Jones, Joshua H; Sweeney, John A et al. (2014) Risperidone and the 5-HT2A receptor antagonist M100907 improve probabilistic reversal learning in BTBR T + tf/J mice. Autism Res 7:555-67