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Relevance to Autism

Comprehensive behavioral characterization of female Ambra1 (+/-) mice in Dere et al., 2014 revealed an autism-like phenotype, including impaired communication and social interactions, a tendency of enhanced stereotypies and repetiive behavior, and impaired cognitive flexibility; these features were absent in male Ambra1 (+/-) mice. Female Ambra (+/-) mice were also shown to display impaired pheromone preference and altered pentylentetrazol-induced seizure propensity in Mitjans et al., 2017. Futhermore, Mitjans et al., 2017 demonstrated, in two independent human cohorts, that the AMBRA1 intronic SNP rs3802890-AA was associated with autistic features in women, who also displayed lower AMBRA1 mRNA expression in peripheral blood mononuclear cells (PBMCs) compared to female GG carriers.

Molecular Function

The protein encoded by the AMBRA1 gene regulates autophagy and development of the nervous system and is involved in autophagy in controlling protein turnover during neuronal development, and in regulating normal cell survival and proliferation.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Heterozygous ambra1 deficiency in mice: a genetic trait with autism-like behavior restricted to the female gender.
Support
Ambra1 Shapes Hippocampal Inhibition/Excitation Balance: Role in Neurodevelopmental Disorders.
Recent Recommendation
Sexual dimorphism of AMBRA1-related autistic features in human and mouse.
ALTs

Rare

No Rare Variants Available

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN981C001 
 intron_variant 
 rs3802890 
 c.2082-183T>C;c.1803-4626T>C;c.2073-183T>C;c.1803-183T>C 
  
 1105 schizophrenia cases (737 male, 368 female; age 39.46 12.58 years) from the Gottingen Research Association for Schizophrenia (GRAS) data collection 
 Discovery 
 GEN981C002 
 intron_variant 
 rs3802890 
 c.2082-183T>C;c.1803-4626T>C;c.2073-183T>C;c.1803-183T>C 
  
 2359 individuals (1144 males, 1215 females; age 49.8 16 years) from the general population 
 Replication 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Deletion-Duplication
 15
 
11
Duplication
 1
 
11
Deletion
 2
 
11
Deletion
 2
 

Model Summary

AMBRA1 heterozygous mutant mice show female specific deficits in social interaction, decreased ultrasound communication in adults and pups, increased tendency for restrictive/repetitive behaviors and reduced cognitive flexibility. AMBRA1 heterozygous mutant mice show no change in viability or fecundity. Sexual dimorphism of the AMBRA1 heterozygous phenotype is partly explained by a strong reduction in AMBRA1 protein in the cerebral cortex of females but not males (Dere et al., 2014).

References

Type
Title
Author, Year
Primary
Heterozygous ambra1 deficiency in mice: a genetic trait with autism-like behavior restricted to the female gender.
Additional
Sexual dimorphism of AMBRA1-related autistic features in human and mouse.

M_AMBRA1_1_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: An embryonic stem cell line containing an insertion of the gene-trap vector pGT1.8geo within the Ambra1 gene was used to generate Ambra1 mutant mice. The Ambra1 genetrap allele was generated as part of a large-scale gene-trap approach for the characterization of genes that play roles in the developing nervous system (PMID 9626495). Ambra1 heterozygous male mice were mated with C57BL/6N female mice that had never given birth before (primipara). .
Allele Type: knockout
Strain of Origin: Not specified
Genetic Background: C57BL/6N
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: A. Stoykova and K. Chowdhury, Max Planck Institute (PMID 17589504, PMID 9626495)

M_AMBRA1_1_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity: Ambulatory activity1
Increased
Description: Mutants show increase in total distance travelled and velocity on the open field compared to controls.
 Open field test
 2.6-2.8 months
Hippocampal morphology2
Increased
Description: Female mutants show enlargement of the hippocampus compared to controls.
 Magnetic resonance imaging (MRI)
 13 months
Brain size2
Increased
Description: Female mutants show enlargement of the whole brain compared to controls.
 Magnetic resonance imaging (MRI)
 13 months
Cerebellar morphology2
Increased
Description: Female mutants show increased cerebellar volume compared to controls.
 Magnetic resonance imaging (MRI)
 3 weeks
Cerebellar morphology2
Increased
Description: Female mutants show increased cerebellar volume compared to controls.
 Magnetic resonance imaging (MRI)
 13 months
Hippocampal morphology2
Increased
Description: Mutants show enlargement of the hippocampus compared to controls.
 Magnetic resonance imaging (MRI)
 3 weeks
Brain size2
Increased
Description: Mutants show enlargement of the whole brain compared to controls.
 Magnetic resonance imaging (MRI)
 3 weeks
Repetitive digging1
Increased
Description: Mutants bury more marbles compared to controls.
 Marble-burying test
 2.6-2.8 months
Circling1
Increased
Description: Mutants circle with increased frequency compared to controls.
 Home cage behavior
 2.6-2.8 months
Seizures2
Increased
Description: Female mutants show increased numbers of tonic-clonic seizures and duration of whole-body seizures compared to controls.
Exp Paradigm: Seizures were induced by single intraperitoneal injection of pentylentetrazol (PTZ) (50mg/kg). Parameters recorded include: (1) hypoactivity: decrease in mobility until rest in crouched or prone position, abdomen at bottom; (2) partial clonus (PC): clonic seizure in face, head or forelimbs; (3) generalized clonus (GC): sudden loss of upright posture, whole-body clonus including all limbs and tail, rearing and autonomic signs; and (4) tonic-clonic seizure (TC): generalized seizure up to tonic hind- limb extension and death. Latencies to (2)??(4) are used to calculate individual seizure scores (ISS).
 Observation of chemically induced seizures
 3 months; 13 months
Seizures2
Decreased
Description: Female mutants display reduced response to PTZ including longer latency to the first whole-body seizure and decreased seizure score compared to female controls.
Exp Paradigm: Seizures were induced by single intraperitoneal injection of pentylentetrazol (PTZ) (50mg/kg). Parameters recorded include: (1) hypoactivity: decrease in mobility until rest in crouched or prone position, abdomen at bottom; (2) partial clonus (PC): clonic seizure in face, head or forelimbs; (3) generalized clonus (GC): sudden loss of upright posture, whole-body clonus including all limbs and tail, rearing and autonomic signs; and (4) tonic-clonic seizure (TC): generalized seizure up to tonic hind- limb extension and death. Latencies to (2)??(4) are used to calculate individual seizure scores (ISS).
 Observation of chemically induced seizures
 3 weeks
Social approach2
Decreased
Description: Female mutant mice show decreased preference for used cage with pheromones whereas control mice prefer used bedding containing pheromones.
Exp Paradigm: Preference between social box with used bedding of C3H mice of opposite gender and another box with only fresh bedding was recorded.
 Olfactory discrimination test
 Not reported
Social memory1
Decreased
Description: Mutants show decreased preference for the unfamiliar mouse compared to controls.
 Three-chamber social approach test
 2.6-2.8 months
Nest building behavior1
Decreased
Description: Mutants show impaired nesting scores including increased weight of leftover nesting material, compared to controls. (Authors infer this is indicative of reduction in social memory.)
 Nest building assay
 2.6-2.8 months
Social interaction1
Decreased
Description: Mutants show decrease in time spent in social interaction compared to controls.
 Reciprocal social interaction test
 2.6-2.8 months
Social approach1
Decreased
Description: Mutants spend less time interacting with an unfamiliar mouse compared to controls.
 Three-chamber social approach test
 2.6-2.8 months
Ultrasonic vocalization: Isolation induced1
Decreased
Description: Mutants show a reduction in the number and duration of calls compared to controls.
 Monitoring ultrasonic vocalizations
 1.1-1.3 weeks
Ultrasonic vocalization: Interaction induced: opposite sex stimulus1
Decreased
Description: Mutants show decrease in the number of calls emitted and longer latency to the first call, compared to controls. Fewer mutant females emit ultrasonic vocalizations compared to wildtype females.
 Monitoring ultrasonic vocalizations
 2.6-2.8 months
Mortality/lethality2
Increased
Description: Females show decreased survival of seizures compared to controls.
Exp Paradigm: Seizures were induced by single intraperitoneal injection of pentylentetrazol (PTZ) (50mg/kg). Parameters recorded include: (1) hypoactivity: decrease in mobility until rest in crouched or prone position, abdomen at bottom; (2) partial clonus (PC): clonic seizure in face, head or forelimbs; (3) generalized clonus (GC): sudden loss of upright posture, whole-body clonus including all limbs and tail, rearing and autonomic signs; and (4) tonic-clonic seizure (TC): generalized seizure up to tonic hind- limb extension and death. Latencies to (2)??(4) are used to calculate individual seizure scores (ISS).
 Observation of chemically induced seizures
 13 months
Exploratory activity1
Increased
Description: Mutants show increased visits to holes on the board compared to controls.
 Hole-board test
 2.6-2.8 months
Cognitive flexibility1
Decreased
Description: Mutants spend more time locating the hidden platform when its location was switched to a different quadrant compared to controls.
 Morris water maze test
 5.6 months
Targeted expression1
Decreased
Description: Mutants show reduced AMBRA1 transcript and protein expression compared to controls. Mutant females show a greater reduction in AMBRA1 protein but not transcript in the cortex, compared to mutant males.
Exp Paradigm:  Western blot
 Western blot
 14 months
Targeted expression1
Decreased
Description: Mutants show reduced AMBRA1 transcript and protein expression compared to controls. Mutant females show a greater reduction in AMBRA1 protein but not transcript in the cortex, compared to mutant males.
Exp Paradigm: Quantitative PCR (qRT-PCR)
 Quantitative PCR (qRT-PCR)
 14 months
Ultrasonic vocalization: Interaction induced: opposite sex stimulus1
 No Change
 Monitoring ultrasonic vocalizations
 2.6-2.8 months
Ultrasonic vocalization: Isolation induced1
 No Change
 Monitoring ultrasonic vocalizations
 1.1-1.3 weeks
Developmental trajectory1
 No Change
 Wire hang test
 0-3 weeks
Size/growth1
 No Change
 Body weight measurement
 2.6-2.8 months; P4, 2 weeks, 2.9 weeks
Anxiety1
 No Change
 Elevated plus maze test
 2.6-2.8 months
Anxiety1
 No Change
 Open field test
 2.6-2.8 months
Depression1
 No Change
 Sucrose preference test
 2.6-2.8 months
Depression1
 No Change
 Forced swim test
 2.6-2.8 months
Exploratory activity1
 No Change
 Hole-board test
 2.6-2.8 months
Response to novelty1
 No Change
 Home cage behavior
 2.6-2.8 months
Cognitive flexibility1
 No Change
 Morris water maze test
 5.6 months
Object recognition memory1
 No Change
 Novel object recognition test
 2.6-2.8 months
Spatial reference memory1
 No Change
 Morris water maze test
 2.6-2.8 months
Spatial working memory1
 No Change
 Morris water maze test
 2.6-2.8 months
Climbing1
 No Change
 Home cage behavior
 2.6-2.8 months
General locomotor activity1
 No Change
 Home cage behavior
 2.6-2.8 months
General locomotor activity: Ambulatory activity1
 No Change
 Elevated plus maze test
 2.6-2.8 months
General locomotor activity: Ambulatory activity1
 No Change
 Open field test
 2.6-2.8 months
General locomotor activity: Ambulatory activity1
 No Change
 Home cage behavior
 2.6-2.8 months
Motor coordination and balance1
 No Change
 Accelerating rotarod test
 2.6-2.8 months
Spontaneous Movement1
 No Change
 Home cage behavior
 2.6-2.8 months
Cerebellar morphology2
 No Change
 Magnetic resonance imaging (MRI)
 3 weeks
Olfactory bulb morphology2
 No Change
 Magnetic resonance imaging (MRI)
 13 months
Olfactory bulb morphology2
 No Change
 Magnetic resonance imaging (MRI)
 3 weeks
Size of cerebral ventricles2
 No Change
 Magnetic resonance imaging (MRI)
 13 months
Size of cerebral ventricles2
 No Change
 Magnetic resonance imaging (MRI)
 3 weeks
Circling1
 No Change
 Home cage behavior
 2.6-2.8 months
Perseveration1
 No Change
 Y-maze test
 2.6-2.8 months
Repetitive digging1
 No Change
 Marble-burying test
 2.6-2.8 months
Seizures2
 No Change
 Observation of chemically induced seizures
 3 weeks
Hearing1
 No Change
 Acoustic startle reflex test
 2.6-2.8 months
Olfaction1
 No Change
 Buried food test
 2.6-2.8 months
Pain or nociception1
 No Change
 Hot plate test
 2.6-2.8 months
Sensorimotor gating1
 No Change
 Prepulse inhibition
 2.6-2.8 months
Startle response: acoustic stimulus1
 No Change
 Acoustic startle reflex test
 2.6-2.8 months
Vision1
 No Change
 Cliff avoidance test
 2.6-2.8 months
Social approach2
 No Change
 Olfactory discrimination test
 Not reported
Social approach1
 No Change
 Three-chamber social approach test
 2.6-2.8 months
Social interaction1
 No Change
 Reciprocal social interaction test
 2.6-2.8 months
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Repetitive behavior, Seizure, Sensory

 

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