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.
1105 schizophrenia cases (737 male, 368 female; age 39.46 12.58 years) from the Gottingen Research Association for Schizophrenia (GRAS) data collection
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.
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)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Ambra1 heterozygous male mice with a gene trap insertion that disrupts protein expression (M_AMBRA1_1_KO_HT, MGI:3715977) were crossed with homozygous PV-Cre females (MGI:3590684) to obtain PV-Cre mice expressing selectively Cre recombinase in parvalbumin-positive interneurons.
Allele Type: Knockout
Strain of Origin: Not specified; 129P2/OlaHsd
Genetic Background: C57BL/6
ES Cell Line: Not specified; E14
Mutant ES Cell Line: Model Source:
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).
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).
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.
Description: Mutant mice exhibited a decrease in social memory compared to wildtype control mice, spending similar amounts of time exploring a novel wildtype female versus a familiar one and displaying a significantly decreased recognition index.
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.)
Exp Paradigm: NA
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.
Exp Paradigm: NA
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).
Description: Mutant mice displayed a decrease in the amount of time spent exploring a novel object compared to wildtype mice, as further shown by a significant reduction in the recognition index.
Description: Mutants spend more time locating the hidden platform when its location was switched to a different quadrant compared to controls.
Exp Paradigm: NA
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
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)
Description: Mutant female mice exhibited a significant reduction in expression of ER-alpha and ER-beta in the hippocampus compared to wildtype mice.
Exp Paradigm: ER-alpha, ER-beta
Description: Mutant mice exhibited a reduction in spine head diameter, an increased percentage of thin spines, and a reduction in the percentage of mushroom spines in CA1 neurons compared to wildtype controls.
Description: Mutant mice exhibited a decrease in social memory compared to control mice, spending similar amounts of time exploring a novel wildtype female versus a familiar one and displaying a significantly decreased recognition index.
Description: Mutant mice displayed a decrease in the amount of time spent exploring a novel object compared to control mice, as further shown by a significant reduction in the recognition index.
Description: Mutant mice exhibited a significant reduction in expression of ER-alpha and ER-beta in the hippocampus compared to vehicle-injected wildtype mice.
Exp Paradigm: ER-alpha, ER-beta
