Recurrent mutations in the PTEN gene have been identified in multiple individuals with ASD as described below. Deleterious variants in PTEN have been identified in individuals presenting with ASD and macrocephaly in multiple studies (PMIDs 15805158, 18759867, 19265751, 20533527). Two de novo deleterious events in the PTEN gene were identified in exome sequencing studies in simplex ASD cases in 2012: a missense variant (p.Thr167Asn) that was classified as "severe" in O'Roak et al. Nature 2012 (PMID 22495309); and a frameshift variant (p.Cys136MetfsX44) in O'Roak et al. Science 2012 (PMID 23160955). A detailed examination of ASD cases with heterozygous PTEN mutations in Frazier et al., 2015 found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). An additional de novo loss-of-function variant in the PTEN gene was subsequently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report furthermore identified PTEN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified PTEN as a gene reaching exome-wide significance (P < 2.5E-06). PTEN has also been designated as a syndromic ASD gene, as mutations in the PTEN gene are causative for Cowden syndrome, a disorder in which a subpopulation of individuals with the syndrome develop autism (PMID 11496368).
Molecular Function
The protein encoded this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
PTEN mutation in a family with Cowden syndrome and autism.
Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics
Interneuron Transplantation Rescues Social Behavior Deficits Without Restoring Wild-Type Physiology in a Mouse Model of Autism With Excessive Synaptic Inhibition
Additional
Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 4-5 of the Pten gene using Nse-cre, authors in PMID 23487788 (Takeuchi K et al 2013) specifically show loss of Pten in granule cells of dentate gyrus and pyramidal neurons of hippocampal CA3 and a subset of postmitotic neruons in the cortex. Same CKOs produced in PMID:16675393
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: E14K
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Exon 4 and 5 are floxed by introducing loxP sites in introns 3 and 5, homozygous mice are obtained by breeding heterozygous knockouts following germline transmission of exon4-5 deletion.
Allele Type: Strain of Origin: Genetic Background: FVB/N *129Sv/Ev* Black swiss
ES Cell Line: Mutant ES Cell Line: Model Source: PMID: 20194734
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exon 5 of the Pten gene , that encodes the phosphatase domain, using Nse-cre (or Enolas2-cre) in neurons of the cortex, hippocampus and cerebellum
Allele Type: Conditional loss-of-function
Strain of Origin: BALB/c
Genetic Background: C57BL/6
ES Cell Line: 129S4/SvJae
Mutant ES Cell Line: Not Specified
Model Source: Not specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 4-5 of the Pten gene using Nse-cre, authors in PMID 23487788 (Takeuchi K et al 2013) specifically show loss of Pten in granule cells of dentate gyrus and pyramidal neurons of hippocampal CA3 and a subset of postmitotic neruons in the cortex. Same CKOs produced in PMID:16675393
Allele Type: Conditional (knockout)
Strain of Origin: Not specified
Genetic Background: C57BL/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Deletion of gene sequence from BglII site in exon 5 to the next BglII site 2.0 kb downstream.
Allele Type: Targeted (knockout)
Strain of Origin: 129Sv/J
Genetic Background: C57BL/6
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 5 of the Pten gene using endogenous Slc6a3 (Dopamine transporter, DAT)-cre, in dopaminergic neurons
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
M3M4 missense double mutations were targeted into the Pten exon 7, which contains the NLS-like sequence.
Allele Type: Targeted (knockin)
Strain of Origin: CD1
Genetic Background: CD1
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
M3M4 missense double mutations were targeted into the Pten exon 7, which contains the NLS-like sequence.
Allele Type: Targeted (knockin)
Strain of Origin: CD1
Genetic Background: CD1
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 5 of the Pten gene using a T2A-cre containing retrovirus injected bilaterally into dentate gyrus at postnatal day 7
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 4-5 of of PTEN using Dlxl12b-cre mice, in gabaergic interneurons of the forebrain, by E15.5. Authors report assessments looking into the secondary progenitor cells of the subventricular zone of the subpallium
Allele Type: Conditional loss-of-function
Strain of Origin: CD1* C56BL/6
Genetic Background: CD1
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exons 4-5 of of PTEN using Dlxl12b-cre mice, in gabaergic neurons of the forebrain, by E15.5. Authors report assessments looking into the secondary progenitor cells of the subventricular zone of the subpallium
Allele Type: Conditional loss-of-function
Strain of Origin: CD1* C56BL/6
Genetic Background: CD1
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 4 - 5 using SST-IRES-Cre, in postmitotic somatostatin expressing cells as they leave the medial ganglionic eminence. The tdtomato reporter under Ai14 Flox/+ line was used to follow expression of the cre recombinase.
Allele Type: Conditional loss-of-function
Strain of Origin: CD1* C56BL/6
Genetic Background: CD1* C56BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exons 4 - 5 using SST-IRES-Cre, in postmitotic somatostatin expressing cells as they leave the medial ganglionic eminence. The tdtomato reporter under Ai14 Flox/+ line was used to follow expression of the cre recombinase.
Allele Type: Conditional loss-of-function
Strain of Origin: CD1* C56BL/6
Genetic Background: CD1
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
In this cell transplant based model, cells from with a homozygous loss of Pten using Dlxl12b-Cre+ were extracted from E12.5 embryos, then transplanted to wild type recipient mice at P1 to see how complete loss of Pten from the secondary progenitors in the subventricular zone (SVZ) of the entire subpallium, affects cell differentiation. The recipient mouse neocortices were then examined 35 days following transplantation.
Allele Type: Conditional loss-of-function
Strain of Origin: CD1* C56BL/6
Genetic Background: CD1
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
In this cell transplant based model, cells from with a heterozygous loss of Pten using Dlxl12b-Cre+ were extracted from E12.5 embryos, then transplanted to wild type recipient mice at P1 to see howpartial loss of Pten from the secondary progenitors in the subventricular zone (SVZ) of the entire subpallium, affects cell differentiation. he recipient mouse neocortices were then examined 35 days following transplantation.
Allele Type: Conditional loss-of-function
Strain of Origin: CD1* C56BL/6
Genetic Background: CD1
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 4-5 of the PTEN gene using Nkx2.1-Cre, in the ventricular zone of the medical ganglionic eminence (MGE) that gives rise to interneurons starting E9.5. The tdtomato reporter under Ai14 Flox/+ line was used to follow expression of the cre recombinase.
Allele Type: Conditional loss-of-function
Strain of Origin: CD1* C56BL/6
Genetic Background: CD1
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exons 4-5 of the PTEN gene using Nkx2.1-Cre in the ventricular zone of the medical ganglionic eminence (MGE) that gives rise to interneurons starting E9.5. The tdtomato reporter under Ai14 Flox/+ line was used to follow expression of the cre recombinase.
Allele Type: Conditional loss-of-function
Strain of Origin: CD1* C56BL/6
Genetic Background: CD1
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 5 of the Pten gene using L7-Cre in Purkinje cells of the cerebellum
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Multifactorial model, Pten CKO mice, with deletion of exons 4 and 5 using GFAP-cre, authors indicate that the is KO localized to the hippocampal granule cells of the dentate gyrus, by P5. These PTEN het CKO mice were treated with 20mg/kg (in 0.9% saline) of kainate (ip) beginning at P60 (2 months age). At approximately 1 hour following saline (control) or kainate injections, all mice received an ip injection of pentobarbital (20mg/kg) to terminate seizure activity. All behavioral testing was carried out 1 week after seizure induction, only mice that had entered the status epilepticus so that they all fell into the category of highest seizure severity were used in the studies.
Allele Type: Multifactorial
Strain of Origin: 129P2/OlaHsd
Genetic Background: FVB*mixed
ES Cell Line: E14K
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Partial loss-of-function knockin mice with truncated Pten gene lacking its C-terminal PDZ motif, Pten^tm(Q399stop)amc, were generated by homologous recombination in iTL1 129S6/SvEvBrdTac(129Sv)-derived embryonic stem cells where residues 399 to 403 were truncated. The PDZ-binding domain was deleted by substituting codon 399 (CAA) with a stop codon (TAA), as previously described (Knafo et al. 2016, PMID 26780512). These mice express normal levels of total Pten protein and normal Pten catalytic activity.
Allele Type: LOF Knockin
Strain of Origin: 129S6/SvEvBrdTac(129Sv)
Genetic Background: C57BL/6
ES Cell Line: 129S6/SvEvBrdTac(129Sv)
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Gain-of-function mutant mice with increased Pten copy number (Pten^tg) that overexpress Pten protein were generated by bacterial artificial chromosome (BAC) transgenesis on a C57BL6/CBA genetic background as previously described in Ortega-Molina et al. 2012, PMID 22405073 (gift from the lab of Manuel Serrano, IRB, Barcelona, Spain).
Allele Type: Overexpression
Strain of Origin: Genetic Background: C57BL6*CBA
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with loxp sites flanking exons 4 and 5 in both alleles of Pten were crossed with Camk2a-Cre heterozygous mice to generate mice with Pten deleted in selectively in the forebrain; M_PTEN_1_CKO_HM; M_PTEN_10_CKO_HM; M_PTEN_12_CKO_HM; M_PTEN_9_CKO_HM
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: Kwon et al, Nat Gen, 2001
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
At P7, Pten^flx/flx animals were co-injected into the dentate gyrus with a retrovirus encoding a fluorophore (mCherry) with a downstream Cre, and a control retrovirus with just a fluorophore (GFP) and no Cre.
Allele Type: Conditional Knockout
Strain of Origin: 129S4/SvJae
Genetic Background: C57BL/6J
ES Cell Line: LW1
Mutant ES Cell Line: Model Source: Hong Wu Lab
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
At P7, Pten^flx/flx animals were co-injected into the dentate gyrus with a retrovirus encoding a fluorophore (GFP) with a downstream Cre, and a control retrovirus with just a fluorophore (mCherry) and no Cre.
Allele Type: Conditional Knockout
Strain of Origin: 129S4/SvJae
Genetic Background: C57BL/6J
ES Cell Line: LW1
Mutant ES Cell Line: Model Source: Hong Wu Lab
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional knockout mice carrying an inducible microglia-specific Pten deletion were generated by crossing Pten^flox/flox mice (MGI:2156086) with Cx3cr1^CreERT2/+ mice (MGI:5450813). The Pten-flox allele contains loxP sites flanking exon 5 of the Pten gene. The knock-in Cx3cr1-CreERT2 allele replaces exon 2 of the microglia-specific gene Cx3cr1 with a tamoxifen-inducible Cre gene (Cre recombinase fused to an estrogen receptor ligand binding domain). The knock-in Cx3cr1-CreERT2 allele also expresses EYFP. The genotype of the experimental mice is Pten^flox/flox;Cx3cr1^CreERT2/+. The genotype of control mice is Cx3cr1^CreERT2/+. Pten deletion in microglia was induced at postnatal days 0-2 (P0, P1, P2) by injection of 50 micrograms of tamoxifen in sunflower oil into the stomach.
Allele Type: Conditional knockout
Strain of Origin: 129S4/SvJae; 129P2/OlaHsd
Genetic Background: ES Cell Line: LW1; E14.1
Mutant ES Cell Line: Model Source: Jackson Laboratory
Description: Dendritic hypertrophy, ectopy, and increased spine density in cerebral cortex and dentate gyri
Exp Paradigm: Golgi staining; immunohistochemistry with antibodies to dendritic markers; electron microscopic analysis of cortex and dentate gyri
Description: Progressive macrocephaly in forebrain; foliation of dg and compression of ca1; increased neuronal size with soma hypertrophy
Exp Paradigm: General observation; hematoxylin/eoslin staining on coronal sections
Description: Hypertrophic and ectopic axonal tract with increased synapses in dentate gyrus
Exp Paradigm: Immunohistochemistry with antibodies to synapsin (presynaptic marker) and calbindin (expressed in soma and processes); electron microscopic analysis of the inner molecular layer of dentate gyri
Description: Increased basal synaptic transmission as measured with input/output relation at dgc synapse
Exp Paradigm: Whole cell recordings in the medial prefrontal pathway
Description: Decreased synaptic plasticity as assessed by impaired tbs-ltp at dgc synapses
Exp Paradigm: Whole cell recordings in the medial prefrontal pathway
Description: Decreased presynaptic function as measured by paired pulse ratio (ppr) at dgc synapse
Exp Paradigm: Whole cell recordings in the medial prefrontal pathway
Description: Decreased synaptic plasticity as assessed through tbs-ltp and hfs-ltp at ca3-ca1 synapses
Exp Paradigm: Whole cell recordings at ca3-ca1 synapses
Description: Decreased synaptic plasticity as assessed through mglur-ltd at dgc synapses
Exp Paradigm: Whole cell recordings in the medial prefrontal pathway
Description: Significantly impaired startle response
Exp Paradigm: Prepulse inhibition of the acoustic startle response as a measure of sensorimotor gating.
Description: Increased phosphorylation of downstream targets of pten such as p-akt, p-s6, p-gsk3, tuberin
Exp Paradigm: Downstream targets phosphorylation
Description: Decreased social novelty as demonstrated by lower novel to total side time ratio and lower time spent sniffing novel mouse normalized by total sniff time
Exp Paradigm: Social novelty preference trial
Description: Decreased sociability demonstrated by decreased time spent with social target with same number of entries towards social side and decreased time spent sniffing social target with no change in sniff frequency
Exp Paradigm: Socialization trial with measures of number of entires and time spent in each side of box, and time spent sniffing each wire cage
Description: Increased nitrative/oxidative stress indicated by increased nitrated tyr in atpase beta-subunit
Exp Paradigm: Mitochondrial enzymaic and complex activity measurement from isolated mitochondria from hippocampus and cerebellum
Cued or contextual fear conditioning: passive avoidance2
Decreased
Description: Mutants show no change in the latency to move to the dark chamber compared to controls that show increase in latency, in the probe stage. mutants show no change in latency to move to the dark chamber in the exposure stage compared to controls.
Exp Paradigm: NA
Description: Decreased synaptic plasticity as assessed through tbs-ltp and hfs-ltp at ca3-ca1 synapses
Exp Paradigm: Whole cell recordings at ca3-ca1 synapses
Description: Decreased synaptic plasticity as assessed through mglur-ltd at dgc synapses
Exp Paradigm: Whole cell recordings in the medial prefrontal pathway
Description: Increased basal synaptic transmission as measured with input/output relation at dgc synapse
Exp Paradigm: Whole cell recordings in the medial prefrontal pathway
Description: Decreased synaptic plasticity as assessed by impaired tbs-ltp at dgc synapses
Exp Paradigm: Whole cell recordings in the medial prefrontal pathway
Description: Decreased presynaptic function as measured by paired pulse ratio (ppr) at dgc synapse
Exp Paradigm: Whole cell recordings in the medial prefrontal pathway
Description: In females, decreased overall activity during dark hours, with fewer rotation but with increased bouts of activity
Exp Paradigm: Wheel running monitoring
Description: divergent growth correlations between brain regions, indicating different patterns of growth between Pten WT and HT mice. Most overgrown areas were the pons, inferior colliculus, and medulla.
Description: Overgrowth in anterior and posterior halves of cortex, in the cerebellum and in the remainder of the brain; only males reported
Exp Paradigm: Measurement of tissue weight
Cued or contextual fear conditioning: memory of context: long term recall3
decreased
Description: male Pten HT froze less in the context test showing impaired remote contextual memory compared to WT males
Exp Paradigm: remote memory for trace fear conditioning
Description: sexual dimmorphism; females are hyerpersensitive (lower startle threshold and increased startle amplitude) to acoustic stimuli of low intensity as juveniles and adults but not as adolescents
Exp Paradigm: low-dB
Description: Pten HT male mice are hyporeactive (low startle amplitude and lower maximum startle response) to acoustic stimuli of high intensity throughout development while female only as adults, not juveniles or adolescent
Exp Paradigm: high-dB
Description: In males, residents exhibit less dominance scores, have fewer discrete attacks, spend less time fighting, and have a greater latency to attack
Exp Paradigm: Resident-intruder test: 15-minute interaction
Description: In males, decreased social habituation, compared to male controls
Exp Paradigm: Reciprocal social interaction test: confined stimulus mouse: juvenile conspecific p21-p28, four 5-minute stimulus presentations, 10-minute intertrial intervals
Description: male Pten HT spend less time than WT investigating the objects across all 3 phases, females Pten HT investigated less than WT in the first phase
Description: In males, decreased latency to light compartment, increased number of crossings between light and dark, more time spent in light compartment, more time spent in center of open field
Exp Paradigm: Open field test
Description: In males, decreased latency to light compartment, increased number of crossings between light and dark, more time spent in light compartment, more time spent in center of open field
Exp Paradigm: Light-dark exploration test
Description: female Pten HT mice showed increased latency to find the platform in the reversal stage, they also only showed trends of spending more time in the platform quadrant compared to WT females which spent significantly more time in the platform quardrant when compared to chance
Description: female Pten HT mice were significantly faster than WT on the tissue task which was not explained by differences in locomotion or anxiety
Exp Paradigm: tunnel, tunnel+bedding, tissue, and foam tasks
Description: female Pten HT mice were significantly faster than WT on the tissue task which was not explained by differences in locomotion or anxiety
Exp Paradigm: tunnel, tunnel+bedding, tissue, and foam tasks
Description: In males, decreased distance traveled during sociability test but not during social novelty test
Exp Paradigm: Three-chamber social approach test
Description: Increased corpus callosum thickness compared to wild type and heterozygote
Exp Paradigm: Immunohistochemistry: mbp for corpus callosum, neun for cortex
Description: Increased ratio of corpus callosum thickness to cortical thickness, compared to wild-types and heterozygotes
Exp Paradigm: Immunohistochemistry: mbp for corpus callosum, neun for cortex
Description: Differential expression of genes related to myelanation, the majority of which were upregulated; out of all differentially expressed genes there is a significant enrichment in myelination-related genes
Exp Paradigm: Rna sequencing of cortical tissue followed by pathway and gene ontology analysis of differentially expressed genes
Description: Increased ratio of corpus callosum thickness to cortical thickness, compared to wild-types
Exp Paradigm: Immunohistochemistry: mbp for corpus callosum, neun for cortex
Dendritic architecture: dendritic tree complexity1
Increased
Description: Increased primary dendrites, number of branching points, number of distal branches, total surface area and dendritic volume
Exp Paradigm: Fluorescence microscopy
Description: Increased neuronal activation of neurons with pten deletion, measured as an increase of phospho-s6
Exp Paradigm: Immunohistochemistry: phospho-s6; fluorescence microscopy
Description: Increased threshold of current delivered to afferent stimulation to fire action potential, increased spike amplitude, more active spike rate
Exp Paradigm: Whole-cell patch clamp
Description: Null expression of pten in neurons infected with retrovirus containing cre, compared to control without cre
Exp Paradigm: Immunohistochemistry: pten; fluorescence microscopy
Description: The neuropils of the parvalbumin +ve neurons extend upto layer i, unlike in wt controls where these projections remain within layerii to vi in mice with pten cko homozygous for sub ventricular zone (svz) derived interneurons
Exp Paradigm: NA
Description: There is a very significant decrease in the number of interneurons in the pten cko homozygous mice, that are believed to be the lineage of the dlxl12b-cre expressing cells. there is an overall reduction of 53% in total number of interneurons in these mouse brains as well
Exp Paradigm: Sst
Description: The loss of pten from the secondary progenitors of the sub ventricular zone in this model leads to increased mortality as the mice die after p18
Exp Paradigm: NA
Description: The transplanted cells lacking pten (pten cko mge cells) recapitulate the phenotype of the donor mice, and have significant reduction in somatostatin expressing interneurons that develop from the pten cko progenitor cells and there is a significant reduction in the ratio of sst/ pv expressing interneurons that develop from the transplants
Exp Paradigm: NA
Description: The resting membrane potential and the action potential threshold is significantly reduced in the transplanted pten cko neurons present in the brain of wt mice
Exp Paradigm: NA
Description: Heterozygous pten cko in mge derived progenitors show decrease in the number of somatostatin expressing interneurons arising from the transplants
Exp Paradigm: NA
Description: The reduction in interneuronal number is biased towards loss of somatostatin (sst) expressing interneurons in the cortex, it is first detectable staring e15.5 and continues to be significant through p30. the ratio of sst/pv expressing interneurons is signficantly reduced.
Exp Paradigm: NA
Description: The neuropils of the parvalbumin +ve neurons extend upto layer i, unlike in wt controls where these projections remain within layerii to vi in mice with pten cko (homozygous) mge derived interneurons
Exp Paradigm: NA
Description: There is a very significant decrease in the number of interneurons in the pten cko homozygous mice, that are believed to be the lineage of the nkx2.1-cre expressing cells. there is an overall reduction of 53% in total number of interneurons, a majority of which occurs in between p0 and p8.
Exp Paradigm: Nkx2.1
Description: The interneurons that express somatostatin and are pten cko homozygous, have a much higher probability of expressing cleaved caspace3
Exp Paradigm: Expression of cleaved caspase-3 (cc3)
Spontaneous post synaptic events: inhibitory currents1
Increased
Description: There is a two fold increase in the frequency of spontaneous ipscs onto layer ii/iii excitatory neurons that are connected to the mge derived interneurons (pten cko, homozygous in this model)
Exp Paradigm: NA
Description: The interneurons that express somatostatin and are pten cko homozygous, have a much higher probability of expressing cleaved caspace3
Exp Paradigm: Cell counting
Description: The pten cko homozygous interneurons had an elevated egg power during behavioral testing in the reciproal social interaction in the gamma frequency band
Exp Paradigm: NA
Description: There is a significant increase in the expression of cleaved caspase3(cc3), an apoptopis marker,in the mfe derived interneurons of the neocortex and lateral cortex marginal zone (nkx2.1-cre/ tdtomato marker expressing). by p0 about 36% of the pten cko homozygous cells express cc3.
Exp Paradigm: NA
Description: Mice with pten cko homozygous mge derived interneurons have significantly reduced preference for a novel mouse compared to control mice
Exp Paradigm: NA
Description: Mice with pten cko homozygous mge derived interneurons ,spend less time exploring the novel object compared to familiar object
Exp Paradigm: NA
Description: There is increased phosphorylated forms of akt (pakt) and gsk3 (pfgsk3) in the medial ganglionic eminence (mge) in mice with pten cko mge interneurons
Exp Paradigm: NA
Description: Older pten cko males show significant reduction in motor coordination, as they have shorter latency to fall from the accelerating rotarod and also do not improve in performance, unlike wild type controls
Exp Paradigm: Males only
Description: Pten ko purkinje cells in have hypertrophic spines, notably in the dendrites that are thicker compared to pcs in wild type mice
Exp Paradigm: Males only
Dendritic architecture: dendritic tree complexity1
Increased
Description: Pten ko purkinje cells have thicker dendrites with more focal dendritic swellings and torpedoes compared to wild type mice, that increase with age in pten cko mice cerebella
Exp Paradigm: Males only
Description: Size of pten ko purkinje cells is increased in all the lobules of the cerebellum by 15% ( 2 months), 50% (4 months) and 60% (9 months)
Exp Paradigm: Males only
Description: There is an increase in the neurofilament content in pten ko purkinje cell compartments, along with an increase in map2 and acetylated alpha-tubulin levels
Exp Paradigm: Males only
Description: By 6 months of age there is a significant reduction in purkinje cell number in the cerebella of pten cko mice, they have about 50% less pcs than wt
Exp Paradigm: Males only
Description: Thickness of the molecular layer is increased in the cerebella of the pten cko mice at 2 and 4 months compared to controls
Exp Paradigm: Males only
Description: By 9 months of age there is a significant increase in the expression of cleaved caspase-3 in the purkinje cells indicative of apoptosis, while wt controls have no expression of cleaved caspase three
Exp Paradigm: Males only
Description: Epscs have increased amplitude in the parallel fiber- purkinje cell synapse (pf-pc) in pten cko mice cerebellar slices
Exp Paradigm: Males only
Description: Epscs have increased amplitude in the climbing fiber- purkinje cell synapse (cf-pc) in pten cko mice cerebellar slices
Exp Paradigm: Males only
Description: Pten cko mice show no preference to stranger mouse over chamber with an object unlike wild type controls
Exp Paradigm: Males only-three-chamber social approach test
Description: Pten cko mice show no preference to stranger mouse over chamber with an object unlike wild type controls
Exp Paradigm: Males only- open field test
Description: Pten cko mice spend significantly less time sniffing, allogrooming or mounting a conspecific female compared to wild type control males
Exp Paradigm: Males only
Description: Pten cko mice have increased signaling in the mtor pathway determined by increase in phosphorylated ribosomal protein s6
Exp Paradigm: Males only
Description: Status epilectus in pten het mice increases distance traveled in the open field as well as in the elevated plus maze as wt controls
Exp Paradigm: Males only- elevated plus maze test
Description: Status epilectus in pten het mice increases distance traveled in the open field as well as in the elevated plus maze as wt controls
Exp Paradigm: Males only-open field test
Description: Status epilectus in pten het mice causes reduced preference for mouse over object in the three chamber test, compared to control pten hets (which have normal preference to mouse )
Exp Paradigm: Males only
Cued or contextual fear conditioning: trace fear conditioning1
Increased
Description: Status epilectus in pten het mice causes increased freezing and learning in the trace fear conditioning test compared to wt and pten het controls
Exp Paradigm: Males only
Description: Mutants show impaired nmdar-dependent synaptic depression (ltd) at cortico-amygdala synapses in the lateral amygdala compared with controls.
Exp Paradigm: Ltd was induced at lateral amygdala synapses in coronal slices by stimulating afferents from the auditory cortex (15 min at 1 hz) and recording the fepsps in the la.
Description: Mutants show decrease in spine density in the la pyramidal neurons and hippocampal neurons, particularly in distal dendrites.
Exp Paradigm: NA
Description: Mutants show decreased excitatory synaptic density in the lateral amygdala and the hippocampus, indicating structural hypoconnectivity.
Exp Paradigm: NA
Description: Mutants show decrease in the number of synapses with large psds in the lateral amygdala. mutants show no change in the average length of the psds in the lateral amygdala.
Exp Paradigm: Lateral amygdala
Neuronal activation following behavioral stimulation1
Decreased
Description: Mutants displayed overall less activity induced by fear conditioning in the auditory cortex. mutants show decrease in glucose uptake in brain areas involved in auditory fear conditioning such as the hippocampus, amygdala, and thalamus, during retrieval of conditional cued memory.
Exp Paradigm: Micro-ct-pet was performed using a radiolabeled glucose analogue (2-deoxy-2-[18f]fluoro-d-glucose, 18ffdg) as the tracer; hippocampus, amygdala, and thalamus.
Description: Mutants show decrease in basal transmission was at synapses receiving thalamic input in the lateral amygdala.
Exp Paradigm: Thalamus; lateral amygdala
Description: Mutants show enhanced synaptic depression at cortico-amygdala (ac-la) synapses compared with controls.
Exp Paradigm: Ltd was induced at lateral amygdala synapses in coronal slices by stimulating afferents from the auditory cortex (15 min at 1 hz) and recording the fepsps in the la.
Description: Mutants show less activity in the frontal and auditory cortices and in the ventral hippocampus.
Exp Paradigm: Micro-ct-pet was performed using a radiolabeled glucose analogue (2-deoxy-2-[18f]fluoro-d-glucose, 18ffdg) as the tracer.
Description: Mutants show increased basal activity in the dorsal hippocampus.
Exp Paradigm: Micro-ct-pet was performed using a radiolabeled glucose analogue (2-deoxy-2-[18f]fluoro-d-glucose, 18ffdg) as the tracer.
Description: Mutants show significantly less ltp at synapses in the auditory cortex - lateral amygdalar pathway.
Exp Paradigm: Auditory cortex; lateral amygdala
Description: Mutants show decreased capacitance in la pyramidal neurons, indicating decrease in total surface area of neuronal membrane.
Exp Paradigm: NA
Description: Mutants made more errors in finding the escape hole during the learning phase (days 1-3) and a higher latency in reaching the escape hole. on the last training day (day 4), mutants show no change in latency in reaching the escape hole, indicating a delay in hippocampal-dependent learning.
Exp Paradigm: NA
Description: When the escape hole was moved to the opposite side of the barnes maze, mutant mice made more errors on day 1 but showed no change on day 2, indicating a delay in hippocampal-dependent learning.
Exp Paradigm: NA
Description: Mutant mice show increase in activity of both mtorc1 measured by the phosphorylation of its downstream target protein s6 at ser 240/244 and mtorc2 measured by the phosphorylation of its downstream target akt at ser 473, in the hippocampus and cortex.
Exp Paradigm: NA
Description: Mutants show a selective increase in phosphorylation of akt-ser473 in the hippocampus but no change in phosphorylation of pkc or ndrg1.
Exp Paradigm: NA
Dendritic architecture: dendritic tree complexity1
Increased
Description: Vehicle-treated Pten knockout neurons had an increased number of intersections. Vehicle-treated Pten knockout neurons have more primary dendrites protruding directly out of the soma compared with their wildtype control. Vehicle-treated Pten knockout neurons displayed an increase in the number of branch points (nodes) and endpoints.
Dendritic architecture: dendritic tree complexity1
Increased
Description: Pten knockout neurons had an increased number of intersections, when compared with wildtype control neurons. Pten knockout neurons have more primary dendrites protruding directly out of the soma, when compared with their wildtype control. Pten knockout neurons had an increased number of branch points (nodes) and endpoints.
Description: The Pten knockout neurons migrate significantly farther from the hilus along the granule cell layer, when compared with their wildtype control.
Exp Paradigm: GFP, mCherry
Description: The total dendritic length was increased in Pten knockout neurons. Pten knockout neurons had increased dendritic growth, confirmed by Sholl analysis of dendritic length.
Exp Paradigm: GFP, mCherry
Description: PTEN mutant mice microglia from both the somatosensory (S1) and auditory (Au1) cortex showed decreased process length, decreased number of branch points, increased volume, and decreased number of terminal points, as compared to controls.
Exp Paradigm: Iba1, software-based morphometric analysis
Description: PTEN mutant mice exhibited a significant reduction in presynaptic VGLUT1 and synaptophysin compared to control synaptosomes, as demonstrated by Western blot.
Exp Paradigm: VGLUT1
Description: PTEN mutant mice exhibited a reduction in VGLUT1 puncta in the deep layers of somatosensory and auditory cortices compared to controls, as demonstrated by immunostaining of tissue sections.
Exp Paradigm: VGLUT1
Description: Excitatory synapses, as identified by colocalized VGLUT1 and PSD95 staining, showed a significantly reduced density in PTEN mutant mice.
Exp Paradigm: VGLUT1, PSD95
Description: The coronal sections of PTEN mutant mice exhibited increased accumulation of microglia compared to controls. This effect was predominantly seen at P14, though the density of microglia in the cerebral cortex remained significantly increased at P30 and 2-3 months in mutant mice.
Exp Paradigm: Iba1
Description: PTEN mutant mice exhibited a significant decrease in presynaptic marker levels (VGLUT1 and synaptophysin) as compared to control synaptosomes. Postsynaptic markers (PSD95, GluN2B, and Gephyrin), on the other hand, showed no significant differences between mutant and control synaptosomes.
Miniature post synaptic current frequency: excitatory1
Decreased
Description: PTEN mutant mice exhibited significantly reduced frequency of miniature excitatory postsynaptic currents compared to controls, as demonstrated by whole-cell patch clamp recordings in L5 pyramidal neurons in the auditory cortex.
Miniature post synaptic current amplitude: excitatory1
Decreased
Description: PTEN mutant mice exhibited significantly reduced amplitude of miniature excitatory postsynaptic currents compared to controls, as demonstrated by whole-cell patch clamp recordings in L5 pyramidal neurons in the auditory cortex.
Description: PTEN mutant mice exhibited increased paired-pulse ratios in L5 pyramidal cells compared to controls. This suggests a decrease in release probability of glutamate vesicles from presynaptic terminals.
Description: PTEN mutant mice exhibited significantly decreased area of miniature excitatory postsynaptic currents compared to controls, as demonstrated by whole-cell patch clamp recordings in L5 pyramidal neurons in the auditory cortex.
Description: PTEN mutant mice spent a decreased amount of time with a companion mouse compared to controls. Controls exhibited a clear preference for interacting with a companion mouse over an inanimate object; in mutant mice, no preference existed.
Description: Mutant mice spent a decreased amount of time exploring a novel mouse compared to controls. Controls exhibited a clear preference for interacting with a novel mouse over a familiar mouse; in mutant mice, no preference existed.
Description: PTEN mutant mice exhibited a decreased amount of time exploring the novel object compared to a familiar object, failing to show a preference for either. Controls, conversely, displayed a significant preference for the novel over familiar object.
Description: Mutant mice microglia exhibited an increase in the number of genes differentially expressed over time. There was an increase in genes encoding C1q components (C1qa, C1qb, and C1qc), and lysosomal KEEG pathway genes (Cd68 and those encoding cathepsins) at P14 and later. DAM signature genes, which reflect an inflammatory microglia state, were also expressed at higher levels in mutant compared to control microglia at P14 and later. Expression of microglia homeostatic genes (P2ry12, Cx3cr1, Cst3, Tmem119, Olfml3, Hexb, Fcrls, Csf1r, Tgfbr1, Mef2a, Mafb) was either unchanged or increased in mutant microglia. Finally, many mitochondria-related genes were expressed at higher levels in mutant microglia from P14 or young adult mice compared to controls.
Description: Western blotting showed that PTEN protein expression in mutant mice microglia was decreased compared to PTEN protein expression in control microglia at both P7 and at 2-3 months.
Exp Paradigm: PTEN
Description: PTEN mutant mice Iba1-positive microglia contained more VGLUT1 puncta within CD68-positive vesicles. This suggests that mutant microglia exhibited increased phagocytosis of VGLUT1-containing pre-synapses in early development.
Exp Paradigm: VGLUT1, CD68
Description: Intracellular staining showed that PTEN mutant microglia largely lost PTEN protein as soon as one week after the tamoxifen injection; this decrease remained consistent through one month.
Exp Paradigm: PTEN
Description: PTEN mutant mice exhibited increased phagocytic capability in microglia compared to controls, as evidenced by an increase in the number of zymosan particles phagocytosed in vitro.
Exp Paradigm: zymosan
Description: Mutant mice exhibited an increase in C1q protein in the somatosensory cortex compared to controls, as shown by immunostaining on tissue sections.
Exp Paradigm: C1q
