RGD Reference Report - Hyperactivity and Hypermotivation Associated With Increased Striatal mGluR1 Signaling in a Shank2 Rat Model of Autism. - Rat Genome Database

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Hyperactivity and Hypermotivation Associated With Increased Striatal mGluR1 Signaling in a Shank2 Rat Model of Autism.

Authors: Modi, Meera E  Brooks, Julie M  Guilmette, Edward R  Beyna, Mercedes  Graf, Radka  Reim, Dominik  Schmeisser, Michael J  Boeckers, Tobias M  O'Donnell, Patricio  Buhl, Derek L 
Citation: Modi ME, etal., Front Mol Neurosci. 2018 Jun 19;11:107. doi: 10.3389/fnmol.2018.00107. eCollection 2018.
RGD ID: 126790534
Pubmed: PMID:29970986   (View Abstract at PubMed)
PMCID: PMC6018399   (View Article at PubMed Central)
DOI: DOI:10.3389/fnmol.2018.00107   (Journal Full-text)

Mutations in the SHANK family of genes have been consistently identified in genetic and genomic screens of autism spectrum disorder (ASD). The functional overlap of SHANK with several other ASD-associated genes suggests synaptic dysfunction as a convergent mechanism of pathophysiology in ASD. Although many ASD-related mutations result in alterations to synaptic function, the nature of those dysfunctions and the consequential behavioral manifestations are highly variable when expressed in genetic mouse models. To investigate the phylogenetic conservation of phenotypes resultant of Shank2 loss-of-function in a translationally relevant animal model, we generated and characterized a novel transgenic rat with a targeted mutation of the Shank2 gene, enabling an evaluation of gene-associated phenotypes, the elucidation of complex behavioral phenotypes, and the characterization of potential translational biomarkers. The Shank2 loss-of-function mutation resulted in a notable phenotype of hyperactivity encompassing hypermotivation, increased locomotion, and repetitive behaviors. Mutant rats also expressed deficits in social behavior throughout development and in the acquisition of operant tasks. The hyperactive phenotype was associated with an upregulation of mGluR1 expression, increased dendritic branching, and enhanced long-term depression (LTD) in the striatum but opposing morphological and cellular alterations in the hippocampus (HP). Administration of the mGluR1 antagonist JNJ16259685 selectively normalized the expression of striatally mediated repetitive behaviors and physiology but had no effect on social deficits. Finally, Shank2 mutant animals also exhibited alterations in electroencephalography (EEG) spectral power and event-related potentials, which may serve as translatable EEG biomarkers of synaptopathic alterations. Our results show a novel hypermotivation phenotype that is unique to the rat model of Shank2 dysfunction, in addition to the traditional hyperactive and repetitive behaviors observed in mouse models. The hypermotivated and hyperactive phenotype is associated with striatal dysfunction, which should be explored further as a targetable mechanism for impairment in ASD.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Shank2Ratadult locomotory behavior  IMP  RGD 
Shank2Ratassociative learning  IMP  RGD 
Shank2Ratresponse to xenobiotic stimulus  IMP  RGD 
Shank2Ratsocial behavior  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SD-Shank2em13SageRatabnormal auditory brainstem response  IMP  RGD 
Shank2Ratabnormal auditory brainstem response  IMP  RGD 
Shank2em13SageRatabnormal auditory brainstem response  IMP  RGD 
SD-Shank2em13SageRatabnormal hippocampal pyramidal neuron dendrite morphology  IMP  RGD 
Shank2Ratabnormal hippocampal pyramidal neuron dendrite morphology  IMP  RGD 
Shank2em13SageRatabnormal hippocampal pyramidal neuron dendrite morphology  IMP  RGD 
SD-Shank2em13SageRatabnormal operant conditioning behavior  IMP  RGD 
Shank2Ratabnormal operant conditioning behavior  IMP  RGD 
Shank2em13SageRatabnormal operant conditioning behavior  IMP  RGD 
SD-Shank2em13SageRatabnormal social investigation  IMP  RGD 
Shank2Ratabnormal social investigation  IMP  RGD 
Shank2em13SageRatabnormal social investigation  IMP  RGD 
SD-Shank2em13SageRatabnormal social play behavior  IMP  RGD 
Shank2Ratabnormal social play behavior  IMP  RGD 
Shank2em13SageRatabnormal social play behavior  IMP  RGD 
SD-Shank2em13SageRatabnormal social recognition  IMP  RGD 
Shank2Ratabnormal social recognition  IMP  RGD 
Shank2em13SageRatabnormal social recognition  IMP  RGD 
SD-Shank2em13SageRatdecreased thigmotaxis  IMP  RGD 
Shank2Ratdecreased thigmotaxis  IMP  RGD 
Shank2em13SageRatdecreased thigmotaxis  IMP  RGD 
SD-Shank2em13SageRatenhanced conditioning behavior  IMP  RGD 
Shank2Ratenhanced conditioning behavior  IMP  RGD 
Shank2em13SageRatenhanced conditioning behavior  IMP  RGD 
SD-Shank2em13SageRatenhanced NMDA-mediated synaptic currents  IMP  RGD 
Shank2Ratenhanced NMDA-mediated synaptic currents  IMP  RGD 
Shank2em13SageRatenhanced NMDA-mediated synaptic currents  IMP  RGD 
SD-Shank2em13SageRathyperactivity  IMP  RGD 
Shank2Rathyperactivity  IMP  RGD 
Shank2em13SageRathyperactivity  IMP  RGD 
SD-Shank2em13SageRatimpaired learning  IMP  RGD 
Shank2Ratimpaired learning  IMP  RGD 
Shank2em13SageRatimpaired learning  IMP  RGD 
SD-Shank2em13SageRatincreased vertical activity  IMP  RGD 
Shank2Ratincreased vertical activity  IMP  RGD 
Shank2em13SageRatincreased vertical activity  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Shank2  (SH3 and multiple ankyrin repeat domains 2)
Shank2em13Sage  (SH3 and multiple ankyrin repeat domains 2; ZFN induced mutant13, Sage)

Genes (Mus musculus)
Shank2  (SH3 and multiple ankyrin repeat domains 2)

Genes (Homo sapiens)
SHANK2  (SH3 and multiple ankyrin repeat domains 2)

Strains
SD-Shank2em13Sage  (NA)


Additional Information