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Relevance to Autism

Astrocyte-specific GLT1 inducible knockout mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes; treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated these pathological repetitive behaviors (Aida et al., 2015). A survey of 31 patients with WAGR (Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation) syndrome caused by de novo 11p14-p12 deletions found that deletion of SLC1A2 occurred in patients with autism more frequently than in those without autism (Xu et al., 2008).

Molecular Function

This gene encodes a member of a family of solute transporter proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.
Positive Association
Association of rare variation in the glutamate receptor gene SLC1A2 with susceptibility to bipolar disorder and schizophrenia.
BPD, SCZ
Negative Association
Analysis of 9p24 and 11p12-13 regions in autism spectrum disorders: rs1340513 in the JMJD2C gene is associated with ASDs in Finnish sample.
Support
De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies.
Epilepsy/seizures
Support
Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism.
WAGR syndrome
ASD, DD, ID
Support
Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN706R001 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R002 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R003 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R004 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R005 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R006 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R007 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R008 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R009 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R010 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R011 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R012 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R013 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R014 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R015 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R016 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R017 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R018 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R019 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R020 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R021 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN706R022 
 missense_variant 
 c.244G>C 
 p.Gly82Arg 
 De novo 
  
  
 GEN706R023 
 missense_variant 
 c.254T>C 
 p.Leu85Pro 
 De novo 
  
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Deletion-Duplication
 25
 
11
Deletion
 2
 
11
Deletion-Duplication
 2
 
11
Deletion
 1
 
11
Deletion
 3
 
11
Deletion
 1
 
11
Deletion
 1
 
11
Deletion
 2
 
11
Deletion
 1
 
11
Deletion
 1
 
11
Deletion
 1
 

Model Summary

Slc1a2 complete knockouts die prematurely, often due to spontaneous seizures and do not reach adulthood, they also demonstrate neuronal degeneration. The conditional KO, specific to astrocytes and activated in adolescent mice, show increased repetitive and stereotypic behavior.

References

Type
Title
Author, Year
Primary
Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.
Additional
Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.

M_SLC1A2_1_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 4 of Slc1a2 gene using Glast-creERT2 (or Slc1a3-cre-ERT2)in astrocytes, after tamoxifen mediated activation of cre at P1
Allele Type: Conditional loss-of-function
Strain of Origin: 129P2/OlaHsd
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_SLC1A2_2_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 4 of Slc1a2 gene using Glast-creERT2 (or Slc1a3-cre-ERT2) in astrocytes, after tamoxifen administration for 5 days, daily, from P19 (adolescent)
Allele Type: Conditional loss-of-function
Strain of Origin: 129P2/OlaHsd
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_SLC1A2_2_CKO_HM_Kainate

Model Type: Pharmaceutical intervention
Model Genotype: Homozygous
Mutation: Adolescent-Slc1a2 CKO mice were treated by intraperitoneal administration of kainic acid (30 mg/kg, Sigma) dissolved in saline, when they were 8-weeks-old, to induce seizures in order to measure seizure susceptibility.
Allele Type: Conditional loss-of-function
Strain of Origin: 129P2/OlaHsd
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_SLC1A2_3_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 4 of the Slc1a2 gene using Glast-creERT2(or Slc1a3-cre-ERT2) in astrocytes, after treatment with tamoxifen for 5 days, daily, from 12 weeks of age (adult CKO)
Allele Type: Conditional loss-of-function
Strain of Origin: 129P2/OlaHsd
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_SLC1A2_1_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Mortality/lethality1
Increased
Description: Early postnatal knock out of Slc1a2 results in premature death of mice
 General observations
 4 weeks
Targeted expression1
Decreased
Description: Early activation of the Cre gene by tamoxifen, at P1 in the Slc1a2 flox/flox mice, leads to almost complete lack of Slc1a2 expression in mice tested at 4 weeks
 Immunohistochemistry
 4 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Repetitive behavior, Seizure, Sensory, Social behavior

M_SLC1A2_2_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Synaptic transmission: excitatory1
Increased
Description: In the repeated stimulation protocol, instead of a decrease in excitatory post synaptic current(EPSC) amplitude seen in control littermates, there is no decrease in the amplitude of EPSC in adolescent-Slc1a2 brain slices, showing increased glutamate release manifested using this protocol
 Repeated minimum stimulation protocol: corticostriatal synapses
 3-4 months
Stereotypy1
Increased
Description: Adolescent-Slc1a2 mice show increased tic-like behavior compared to littermate controls
 General observations: novel environment
 4 months
Self injurious behavior1
Increased
Description: Sustained high levels of self-grooming leads to skin lesions in adolescent-Slc1a2 mice
 
 3 months
Self grooming: perseveration1
Increased
Description: Adolescent-Slc1a2 mice show increased self grooming, leading to the formation of skin lesions starting 8- 9 weeks of age
 Grooming behavior assessments: home cage and novel environment
 8-9 weeks
Targeted expression1
Decreased
Description: Adolescent-Slc1a2 KO mice show 60-80% reduction in the targeted Slc1a2 protein confirming loss of gene expression
 Immunohistochemistry
 7 weeks
Anxiety1
 No Change
 Light-dark exploration test: Light-dark exploration test
 4 months
Anxiety1
 No Change
 Elevated plus maze test
 4 months
Inflammatory response1
 No Change
 Histology: Histology
 3 months
Brain size1
 No Change
 
 8-9 weeks
Neuronal number in the brain1
 No Change
 Immunohistochemistry: fluorescence microscopy
 4 months
Neuroreceptor levels: glutamate receptors: AMPA receptors1
 No Change
 Western blot
 16 weeks
Neuroreceptor levels: glutamate receptors: NMDA receptors1
 No Change
 Western blot
 16 weeks
Neuronal activation following behavioral stimulation: c-Fos levels1
 No Change
 Immunohistochemistry: thalamus, medial prefrontal cortex
 4-5 months
Neurotransmitter release1
 No Change
 Microdialysis
 3-4 months
Synaptic neuroreceptor ratio (NMDAR/AMPAR) dependent transmission1
 No Change
 Whole-cell patch clamp: corticostriatal synaptic transmission
 3-4 months
Synaptic transmission: excitatory1
 No Change
 Whole-cell patch clamp: corticostriatal synaptic transmission
 3-4 months
Electroencephalogram (EEG): signature of seizure/epilepsy1
 No Change
 Electroencephalogram (EEG)
 4-5 months
Pain or nociception1
 No Change
 Hot plate test
 7 months
Social approach1
 No Change
 Three-chamber social approach test
 6 months
Social interaction1
 No Change
 Reciprocal social interaction test
 5 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Homeostasis, Learning & memory, Maternal behavior, Motor phenotype

M_SLC1A2_2_CKO_HM_Kainate

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Seizure threshold1
Decreased
Description: Kainate injected mutant Slc1a2 mice show increased seizure sensitivity or decreased threshold of seizure induction compared to littermate controls, determined using a scoring system of 1-7 level of seizures with a higher percentage of mutants expressing a score of 7(death)
 Observation of chemically induced seizures
 8 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Repetitive behavior, Sensory, Social behavior

M_SLC1A2_3_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General characteristics1
 No Change
 General observations
 5 months
Targeted expression1
 No Change
 Immunohistochemistry
 5 months
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Repetitive behavior, Seizure, Sensory, Social behavior

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