According to a review (Dykens and Volkmar, 1997) of 14 studies, the percentages of individuals with Fragile X syndrome who met criteria for autism varied from 5 to 60%, with 7 studies finding more than 20%. As well, polymorphisms in the FMR1 gene have been found to be associated with autism. However, other studies have found no genetic association or only relatively rare identification of FMR1 with autism. Separately, several studies have found a CGG repeat polymorphism as well as rare variations in the FMR1 gene identified with Fragile X syndrome and general cognitive function.
Molecular Function
The protein encoded by this gene binds RNA and is associated with polysomes. The encoded protein may be involved in mRNA trafficking from the nucleus to the cytoplasm.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmenta...
Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Purkinje cell specific knock out of FMR1, using L7-cre mice.
Allele Type: Knockout
Strain of Origin: Genetic Background: mixed
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous; hemizygous
Mutation:
FMR1 mutant gene was generated by construction a targeting vector using homologous recombination against Exon 5 which was interrupted by the positive selection marker gene neomycin (neo). FMR1 homozygous knockout mice (FMR1^tm1Cgr) were bred with NeuroD1 bacTRAP (ND1-BT) heterozygous mice (PMID 28823556) to generate FMR1 and ND-BT1 dual heterozygous female mice that were bred with FMR1-/y male mice to generate FMR1 null and ND1-BT heterozygous (FMR1-/-;ND1-BT+/-) that were used for experimentations.
Allele Type: Knockout
Strain of Origin: 129P2/OlaHsd
Genetic Background: C57BL/6J
ES Cell Line: E14
Mutant ES Cell Line: Not specified
Model Source: The Jackson Laboratory
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A germline null mutation was created by crossing FMR1 mice, which has the first coding exon floxed, with mice that express Cre-recombinase in the germline (Tg(CAG-cre)13Miya). Gene inactivation was confirmed by a lack of protein expression in the brain and testes as determined by immunoblot analysis.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: 129P2/OlaHsd * C57BL/6
ES Cell Line: E14
Mutant ES Cell Line: Not specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 1 of FMR1 using L7-cre, in Purkinje cells of the cerebellum
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6J
Genetic Background: Not specified
ES Cell Line: E14
Mutant ES Cell Line: Not specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
FMR1 KO mice, floxed at exon 5, maintained in the mixed background of C57Bl/6 and 129P2.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6.129P2
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
FMR1 gene was generated by construction a targeting vector using homologous recombination against Exon 5 which was interrupted by the positive selection marker gene neomycin (neo).
Allele Type: Knockout
Strain of Origin: 129P2/OlaHsd
Genetic Background: Not Specified
ES Cell Line: E14
Mutant ES Cell Line: Not specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Homologous recombination mediated introduction of I304N mutation to FMR1 locus.
Allele Type: Humanized LOF mutation
Strain of Origin: Not Specified
Genetic Background: FVB x C57BL/6J
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
FMR1 KO mice with a mixed FVB and 129P2 background(information not available for pde6b+.
Allele Type: Knockout
Strain of Origin: Genetic Background: FVB.129P2
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Knock in of transgene containing ~120 CGG.CCG repeats in the FMR1 gene with a Cre recombinase under the control of the MMTV promoter.
Allele Type: Humanized LOF mutation
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:
Homozygous
Mutation:
FMR1 KO mice were originally on the C57Bl/6 background but to generate phenotyped in a mixed C57BL/6 129SveJ background form litters.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6.129SVeJ
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Homologous recombination against Exon 5 which was interrupted by the positive selection marker gene neomycin, maintained in a mixed background with FVB and 129P2 corrected for eyesight by the pde6b allele.
Allele Type: Knockout
Strain of Origin: Not Specified
Genetic Background: FVB.129P2.pde6b+
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Pharmaceutical intervention
Model Genotype:
Homozygous
Mutation:
Postnatal day 14 to 29 d old mice were anesthetized by an i.p. injection of 10mg/kg ketamine and 2mg/kg xylazine. A GluA1-GFP viral contruct was injected through a glass pipette, stereotaxically into the hippocampal CA1 region. For behavioral tests 10-12 injections of 6 ul high titer viral solutions were delivered along the entire hippocampus of both sides to achieve expression in one third of the CA1 pyramidal neurons. A cocktail of 5HT and Dopamine receptor agonist and antagonist was coadministered. The 5HT 2B-R agonist BW723C86 (0.05mg/kg) and 5HT 2A-R-Antagonist MDL11939 (0.01mg/kg)The D1- R agonist SKF81297 (0.05mg/kg) and D2-R antagonist Sulpiride (0.25mg/kg) were administered by four i.p. injections spaced by 4-6 h. The administration started 4-10 h before the viral injection and 16-20 h before behavioral tests. The compounds were dissolved in saline and saline was given to vehicle controls.
Allele Type: Knockout
Strain of Origin: 129P2/OlaHsd
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: JAX
Model Type:
Pharmaceutical intervention
Model Genotype:
Homozygous
Mutation:
Postnatal day 14 to 29 d old mice were anesthetized by an i.p. injection of 10mg/kg ketamine and 2mg/kg xylazine. A GluA1ct-GFP viral contruct was injected through a glass pipette, stereotaxically into the hippocampal CA1 region. The GluA!ct is a GFP taged cytiplasmic domain of GluA1 receptor subunit that acts as a dominant negative construct selectively blocking synaptic trafficking of endogenous or viral GluA1 contianing AMPA-rs.
Allele Type: Knockout
Strain of Origin: 129P2/OlaHsd
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Hemizygous (Fmr1), heterozygous (Syngap1)
Mutation:
Syngap1 het mice were mated with FMR1-/+ females to get FMR1-/y:Syngap1+/- mice.
Allele Type: Knockout
Strain of Origin: 129P2/OlaHsd*C57BL/6JOla
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous; hemizygous
Mutation:
FMR1 knockout mice on the FVB/NJ background. (Construct details not available).
Allele Type: Knockout
Strain of Origin: Not Specified
Genetic Background: FVB/NJ
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Lugo Lab, Baylor University (PMID 28915148)
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
Seven-week-old wildtype C57BL/6 male mice were injected with Fmr1-siRNA (1358762, NM_008031.2), bilaterally in the dorsal striatum using a stereotaxic apparatus, resulting in a reduction of Fmr1 transcript levels to 0.4 fold compared with control siRNA injected mice.
Allele Type: Knockdown
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: Daehan BioLink (Eumsung, Chungbuk, Republic of Korea)
Model Type:
Genetic
Model Genotype:
Homozygous/Hemizygous
Mutation:
FMR1 mutant gene was generated by construction a targeting vector using homologous recombination against Exon 5 which was interrupted by the positive selection marker gene neomycin (neo). FMR1 homozygous knockout mice (FMR1^tm1Cgr) were bred with NeuroD1 bacTRAP (ND1-BT) heterozygous mice (PMID 28823556) to generate FMR1 and ND-BT1 dual heterozygous female mice that were bred with FMR1-/y male mice to generate FMR1 null and ND1-BT heterozygous (FMR1-/-;ND1-BT /-) that were used for experimentations; M_FMR1_1_KO_HM
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Not specified
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
Fmr1 ko mice with a deletion of the promotor and the first exon.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Description: No difference in time spent in each compartment however much more line crossings in the lit compartment
Exp Paradigm: Movement in and between two compartments (one lit and one dark) of a box
Description: Increased testicular weight without structural differences at four different ages; total weight and weight of kidney, heart, spleen, and liver were not statstically different
Exp Paradigm: General observation; light microscopic examination
Description: The juvenile fmr1 ko mice show increased hyperactivity in the open field test measured by the number of line crossings
Exp Paradigm: Three-chamber social approach test
Description: The juvenile fmr1 ko mice show increased hyperactivity in the open field test measured by the number of line crossings
Exp Paradigm: Open field test
Description: Increased general locomotor activity indicated by increased travel distance, travel speed, no. of line crossings, distance travelled in centre zone
Exp Paradigm: Open field test
Description: The apical dendrites of layer v pyramidal neurons from visual cortex of fmr1 ko mice have higher spine density than wild type mice
Exp Paradigm: Quantification using light microscope of sections fixed and mounted after being impregnated with golgi-cox
Description: Increased numbers of inhibitory synapses as indicated by puncta positive for gephyrin and vgat
Exp Paradigm: Immunostaining analysis for gephyrin and vgat
Description: Mutants show decrease in dendritic length compared to controls. mutants show no change in the dendritic length per branch order compared to controls.
Exp Paradigm: Dendritic complexity was quantified using dendritic length, number of intersections within sholl radii (10m concentric circles), and mean dendritic length/number of branches per branch order. cells were filled with biocytin to vidualize dendrites.
Description: Decreased numbers of excitatory synapses as indicated by puncta positive for psd95 and vglut
Exp Paradigm: Immunostaining analysis for psd95 and vglut
Description: Disruption of normal functioning of parvocellular oxytocin neurons (fluoro-gold nagative, shoulder negative based on shape of membrane depolarization preceeding action potential) but not magnocellular oxytocin neurons (fluoro gold positive) in the pvn of the hypothalamus
Dendritic architecture: dendritic tree complexity14
Decreased
Description: Mutants show decrease in the number of intersections and dendritic branchings, compared to controls. mutants show a decrease in the number of dendritic branches in the tertiary branch order, compared to controls.
Exp Paradigm: Dendritic complexity was quantified using dendritic length, number of intersections within sholl radii (10m concentric circles), and mean dendritic length/number of branches per branch order. cells were filled with biocytin to vidualize dendrites.
Description: Increased gp1 mglu-mediated hippocampal ltd
Exp Paradigm: Extracellular field potentials were recorded in stratum radiatum of ca1 in response to schaffer collateral stimulation from hippocampal slices
Miniature post synaptic current amplitude: excitatory14
Decreased
Description: Mutants show decreased nmda receptor-mediated epscs in the dg than those in controls.
Exp Paradigm: Nmda receptor-mediated epscs were obtained by holding cells at +40 mv, while 0.05 ms pulses.
Description: Mutants show decreased slope of nmdar-mediated epsc curve at stimulation intensities ranging between 0.3 and 1.9 ma, compared to controls.
Exp Paradigm: Input-output relationships for the epsc amplitude were measured as a function of afferent fiber stimulus intensity. nmda receptor-mediated epscs were obtained by holding cells at +40 mv, while 0.05 ms pulses.
Description: Increased maximum transient depression (mtd) in response to dhpg
Exp Paradigm: Extracellular field potentials were recorded in stratum radiatum of ca1 in response to schaffer collateral stimulation from hippocampal slices
Description: Increased acoustic startle reflex manifesting as whole body startle response
Exp Paradigm: Response to short auditory stimuli of moderate intensity
Description: Increased social approach evident by increased number of nose contacts with stimulus mouse
Exp Paradigm: Quantification of nose contacts with s1 stimulus mouse after chronic lithium treatment
Description: Increased social preference indicated by social preference for s2 after treatment
Exp Paradigm: Comparison of interaction with familiar s1 mouse and novel s2 mouse after chronic lithium treatment
Description: Decreased social interaction demonstrated by no significant preference for stimulus mouse
Exp Paradigm: Chambered social interaction paradigm; resident-intruder paradigm-reciprocal social interaction test
Description: Increased sociability demonstrated by increased time spent in chamber 1
Exp Paradigm: Measurement of preference for chamber with an introduced mouse in social interaction apparatus after chronic lithium treatment
Description: Decreased social interaction demonstrated by no significant preference for stimulus mouse
Exp Paradigm: Chambered social interaction paradigm; resident-intruder paradigm- resident-intruder test
Description: Lack of social preference indicated by no significant preference for novel mouse compared to familiar mouse
Exp Paradigm: Comparison of interaction with familiar s1 mouse and novel s2 mouse
Description: Decreased social interaction indicated by decreased duration of nose contacts with s1 mouse
Exp Paradigm: Quantification of duration of nose contacts with s1 stimulus mouse
Description: Fmr1 ko mice spend more time in the light chamber and have more gate crossings showing reduced anxiety
Exp Paradigm: The dark chamber was not illuminated and the light chamber was illuminated with a fluorescent light. mice were placed in the dark chamber for 2 min. the divider separating the two chambers was then removed and the mice were allowed to freely investigate both chambers for 10 min. the time spent in the light chamber and the number of gate crossings in the light-dark box were recorded
Description: Decreased anxiety levels in elevated plus maze and also demonstrated by increased distance travelled in center of open field
Exp Paradigm: Elevated plus maze test-elevated plus maze test
Description: Decreased anxiety levels in elevated plus maze and also demonstrated by increased distance travelled in center of open field
Exp Paradigm: Elevated plus maze test- open field test
Description: Increased anxiety demonstrated by increased time rearing and digging during social preference period
Exp Paradigm: Observation during social preference
Description: Fmr1 knockout mice show increased preference for the outer zone versus the inner zone of the open field compared to controls.
Exp Paradigm: NA
Description: Fmr1 ko mice spend more time in the open arms in the elevated plus maze showing reduced anxiety
Exp Paradigm: Time spent in the open arms of the plus maze was recorded. mice were placed in the center of the maze and allowed to freely explore the covered and the open arms
Description: Decreased anxiety measured by increased time spent and distance traveled in the center of chamber
Exp Paradigm: Open field test for both male and female
Description: Fmr1 knockout mice show reduced discrimination index between a novel and familiar object 1 day after initial exposure, compared to controls.
Exp Paradigm: NA
Description: Fmr1 ko mice show reduced (but insignificant) freezing in the contextual fear conditioning paradigm comapred to wt controls
Exp Paradigm: The standard fear conditioning training consisted of a 3 min exposure of mice to conditioning box (context) followed by a foot shock, after a preceding tone (30 s, 3khz, 75db). the memory test is performed after 24 h by re exposing the animals for 5 min to the conditining context and 1 h later to a novel context for 3 min followed by a tone( 3 min, 3 khz, 75 db)
Description: Mutants spent less time exploring compared to controls, indicating impairment in dg-dependent pattern separation learning.
Exp Paradigm: NA
Description: Fmr1 ko mice show reduced learning in the conditional cue dependent choice task, wt mice progressively learned the task
Exp Paradigm: Y maze learning test was carried out using an elevated y maze, one start arma nd two goal arms. the food well located at the end of each goal arm was filled with sucrose sweetened non fat dairy milk as a reward. after 18 h food fasting with no restriction on water access, mice were first habituated to y maze and milk reward. mice were then trained and tested on a conditional learning task using interchangeable floor inserts, either plain or white or black wire mesh, covering the whole of the start arm, this was the conditional cue. the presence of the plain white insert indicated the presence of milk reward in the right goal arm and the black wire mesh indicated the milk reward was present in the left arm. mice received 14 training sessions consisting of 10
Description: Fmr1 ko mice show significantly reduced freezing in the more demanding associative learning in trace fear conditioning paradigm comapred to wt controls
Exp Paradigm: Trace fear conditioning traning consisted of a 15-sec white noise conditioned stimulus (cs) and a 0.5 s scrambled foot shock (us). mice were acclimated for 60 sec and then presented with seven cs-trace-us intertrial interval trials ( trace, 30 sex, iti, 210 sec). one day after training, mice were acclimated for 60 sec followed by 7 cs iti trials ( iti, 30 sec) in a novel chamber to test for trace fear memory.
Description: Mutants show a decrease in the levels of psd-95 (dlg4) in the synaptoneurosome fraction of the dentate gyrus, compared to controls, but not in the whole tissue lysate of the dentate gyrus.
Exp Paradigm: NA
Description: Decreased expression of gabaa receptor subunit in neocortex and hippocampus. no change in cerebellum, caudate putamen, thalamus, and bulbus olfactorius
Exp Paradigm: Gabaa receptor subunit gene expression
Description: Mutants show increase in akt phosphorylation (pakt/akt levels) in the synaptoneurosomal fraction of the dentate gyrus but not the whole lysate of the dentate gyrus or the whole lysate of the hippocampal ca1 region, compared to controls. mutants show increase in erk phosphorylation (perk/erk levels) in the synaptoneurosomal fraction of the dentate gyrus but not the whole lysate of the dentate gyrus or the whole lysate of the hippocampal ca1 region, compared to controls.
Exp Paradigm: NA
Description: Fmr1 knockout mice show increased transcript levels for nr4a1, shank2, arc and gria1 in the cerebral cortex compared to controls.
Exp Paradigm: NA
Description: Fmr1 knockout mice show increased phosphorylation of brd4 indicating that increased levels of brd4 in fmr1 mutants correlates with increased levels of activated brd4.
Exp Paradigm: NA
Description: Abnormal gene expression profile indicating the dysfunction of parvocellular ot neurons; asd risk and fmrp target genes are enriched in parvocellular ot neurons
Description: Fmr1 knockout mice show increased expression of fmrp target proteins, including brd4, mll1, and p300, compared to controls.
Exp Paradigm: NA
Description: Fmr1 knockout mice show widespread misregulation of transcription with more genes increased than decreased compared to controls. changes in gene expression were highly correlated with changes in h3k4me3 and h3k27ac levels in fmr1 knockout mice. upregulated genes were typically high expressers and included synaptic proteins and receptor proteins. downregulated genes in fmr1 mutants included transcriptional regulators. genes misregulated in fmr1 mutant mice show a significant overlap with asd genes.
Exp Paradigm: NA
Description: Fmr1 ko mice have elevated basal levels of ras-gtpduring sleeping and reduced ranges of ras activation between sleeping and awake states comapred to wt mice. both wt and fmr1 ko mice had increased ras-gtpin awake states
Exp Paradigm: Protein modification
Description: There is decreased signal transduction between ras gtpto pi3/pkb proteins in fmr1 ko mice, as there is decreased phosphorylated pkb in the awake state in the ko mice, whereas there is increased phosphorylated pkb in wt mice in the awake state.
Exp Paradigm: Signaling
Chromatin modification: histone modification: open chromatin13
Increased
Description: Fmr1 knockout mice show increased histone modifications associated with active chromatin compared to controls, including h3 lysine 4 trimethylation (h3k4me3), h3 lysine 27 acetylation (h3k27ac), and h4 lysine 8 and 16 acetylation (h4k8ac and h4k16ac). fmr1 knockout mice show increased h3k4me3 at nr4a1 and shank3 and throughout the genome with increased abundance at transcription start sites, and increased h3k27ac in neurons, compared to controls.
Exp Paradigm: NA
Description: Hippocampal slices of newborn and young fmr1 ko pups showed bursting activity and a four-fold increase in spontaneous excitatory postsynaptic currents
Exp Paradigm: NA
Description: Brain slices extracted from early postnatal fmr1 ko pups show increased field potential recordings after treatment with gabaa r agonist: isoguvacine, unlike slices from wt littermates
Exp Paradigm: Field potential recordings of slices treated with isoguvacine
Description: Fmr1 ko mice show a continued elevated driving force of gabaa receptor (chloride ion channel) in fetal neurons from embryonic day 20- 21 through post natal day 15 and 30, unlike wt littermates who had elevated driving force only during the embryonic stages and showed a reduction in the driving force in early post natal stages.
Exp Paradigm: NA
Description: Neurons extracted from newborn fmr1 ko pups show increased spike ( action potential) frequencies when treated with the gabaa r agonist: isoguvacine, unlike wt littermate neurons, that did not show an increased spike frequency following the treatment.
Exp Paradigm: Cell attached recordings of slices treated with isoguvacine
Description: Drastically reduced levels of fmr1 transcripts in brain and of the fmrp
Exp Paradigm: M_fmr1 gene expression- quantitative pcr (qrt-pcr): brain
Description: Drastically reduced levels of fmr1 transcripts in brain and of the fmrp
Exp Paradigm: M_fmr1 gene expression-immunocytochemistry: brain or testis by using anti-fmrpantibody
Description: Increased number of parvalbumin (pv) neurons in layers v and vi in somatosensory cortex
Exp Paradigm: Double immunohistochemistry and dapi staining of the somatosensory cortex using anti-pv antibody
Description: Decreased number of parvalbumin (pv) neurons in layers ii/iii and iv in somatosensory cortex
Exp Paradigm: Double immunohistochemistry and dapi staining of the somatosensory cortex using anti-pv antibody
Description: Decreased trkb protein expression as demonstrated by decreased number of puncta oriented perpendicularly to pia surface and reduction in total number of trkb positive puncta
Exp Paradigm: Trkb protein expression
Description: Increased spontaenous locomotor activity demonstrated by greater distance traveled and greater average velocity
Exp Paradigm: Open field test
Description: Decreased excitatory postsynaptic current amplitude after application of dhpg indicative of enhanced mglur-ltd
Exp Paradigm: Whole cell recordings of hippocampal cultures
Description: Tactile prepulse inhibition responses are enhanced in fmr1 ko mice, as opposed to control littermates that display reduced magnitude of acoustic startle response when they receive an air puff prepulse
Exp Paradigm: NA
Description: Fmr1 kos have reduced discrimination and memory for objects differing in texture (rough or smooth) and do not preferentially interact with a novel textured-object over a familiar one
Exp Paradigm: NA
Description: Increased sensorimotor gating measured by prepulse inhibition with all prepulses, but more pronounced with lower decibel
Exp Paradigm: Prepulse inhibition test
Description: Macroorchidism indicates deficits in reproductive system development
Exp Paradigm: General observation; light microscopic examination-general observations
Description: Macroorchidism indicates deficits in reproductive system development
Exp Paradigm: General observation; light microscopic examination- histology: testis
Description: Fmr1 kosmice have reduced preference for novel object when the retention period (or interval) is extended to 1 hr from 5 min, whereas wt mice still prefer the novel object
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of cue2
Decreased
Description: Decreased cued conditioning learning measured as freezing patterms
Exp Paradigm: Cued fear conditioning test after intraperitoneal administration of thip(10 mg/kg)
Description: Decrease in the total area covered by mitochondria in synapses; no change in mitochondrial area per synapse area, indicating that mitochondrial size was scaled to the smaller synapse size
Description: Increased multi-conductance, voltage-dependent channel activity in brain smvs indicating that lack of sequestration of h+ ions in the acma assay was due to leaky smv membranes
Mitochondrial ATP synthesis coupled electron transport2
Decreased
Description: Submitochondrial vesicles failed to sequester h+ ions in response to atp addition, indicating either a failure of the enzyme to translocate h+ or an h+ leak in the submitochondrial vesicle membranes; slight decrease in atp levels
Mitochondrial proton-transporting ATP synthase complex, catalytic sector F(1)
Increased
Description: Increased levels of atp synthase b-subunit (f1) mrna, indicating although loss of fmrp may lead to enhanced transcription of both b and c-subunit mrnas, in contrast only b
Description: Increase in glycolytic enzymes including hexokinase ii, pyruvate kinase m2 variant and lactate dehydrogenase measured by labeling newly synthesized proteins with puromycin and immunoprecipitating with an anti-puromycin antibody
Description: Increased mtor kinase activity demonstrated by increased association of mtor with raptor in hippocampal slices
Exp Paradigm: Mtor kinase activity
Description: Disruption of synaptic stimulation-induced changes in protein synthesis in synaptosomes ; decrease in synaptic-stimulation induced increase in atp synthase b-subunit (f1) protein synthesis compared with controls
Description: Increased phosophorylation of 4e-bpand association of eif4g with eif4e in hippocampal slices
Exp Paradigm: Eif4f transcription initiation complex formation
Description: Increase in enzymes of tricarboxylic acid cycle and nad+/nadh metabolism, including enzymes of the malate/aspartate shunt and isocitrate dehydrogenase measured by labeling newly synthesized proteins with puromycin and immunoprecipitating with an anti-puromycin antibody
Description: Increased dendritic spine density in neurons in medial prefrontal cortex, dorsal hippocampus, basal lateral amygdala
Exp Paradigm: Males only
Dendritic architecture: dendritic tree complexity1
Decreased
Description: Decreased arborization of dendrites in layer iii pyramidal neurons, ca3 pyramidal cells, and pyramidal and stellate cells in basal lateral amygdala
Exp Paradigm: Males only
Description: Deficit in developmental trajectory demonstrated by increased testicular weights, which is not normal in the development of reproductive organs
Exp Paradigm: NA
Description: Decreased anxiety indicated by more time spent in open quadrants in epm and indicated by fraction of distance traveled in margins of field in open field test
Exp Paradigm: Elevated zero maze test-elevated zero maze test
Description: Decreased anxiety indicated by more time spent in open quadrants in epm and indicated by fraction of distance traveled in margins of field in open field test
Exp Paradigm: Elevated zero maze test- open field test
Cued or contextual fear conditioning: passive avoidance1
Decreased
Description: Decreased latency to enter the dark compartment 24hours after training in the passive avoidance task, compared to wild type
Exp Paradigm: Passive avoidance task
Description: Increased rate of cerebral protein synthesis (rcps) as measured across various brain regions including dorsal/ventral hippocampus and cortical areas
Exp Paradigm: Cerebral protein synthesis rate
Description: Abnormal spine morphology of pyramidal neurons in hippocampal area ca1 with higher fraction of fliopodia-like and thin spines compared to stubby and mushroom spines
Exp Paradigm: Males only
Description: Deficit in developmental trajectory demonstrated by increased testicular weights, which is not normal in the development of reproductive organs
Exp Paradigm: Males only
Description: Increased phosphorylation of key translational control molecules - s6 at 240/244 and 235/36 phosphorylation sites, eif4b, mtor, erk in whole hippocampal lysates
Exp Paradigm: Males only
Description: Increased locomotor activity indicated by greater distance traveled, more distinct horizontal movement, and more time spent moving
Exp Paradigm: Open field test
Description: Increased mean density of apical dendritic spines in segment 3 without changes in segments 1-2 and 5-10
Exp Paradigm: Golgi staining procedure of pyramidal cells in cortical layers ii/iii of temporal lobe
Description: Mutants show reduced spontaneous spiking of l2/3 fast spiking units but show no change in spontaneous spiking of regular spiking units in the vrc compared with controls.
Exp Paradigm: Ventra retrosplenial cortex
Description: Mutants show increased evoked spike rate in l2/l3 pyramidal neurons of the s1 somatosensory cortex compared with controls.
Exp Paradigm: NA
Description: Mutants show decrease in whisker evoked population firing rate in l2/3 rs cells compared with controls. mutants show decrease in the fraction of whisker responsive l2/l3 regular spiking units compared with controls. mutants show a decrease in pairwise tuning similarity (signal correlation) between simultaneously recorded l2/3 rs neurons , reduced noise correlation and reduced firing synchrony compared with controls.
Exp Paradigm: Single unit fast and regular spikes were recorded in c1-2 and d1-2 whisker columns in the vrc (ventral retrosplenial cortex) with laminar polytrodes in l4 and l2/3 of s1 in adult urethane-anesthetized mice (p42-92). spiking was measured in response to calibrated whisker deflections.
Description: Mutants show increase in e-i conductance ratio compared with controls, indicating a greater decrease in ipsc than epsc.
Exp Paradigm: L4-evoked feedforward excitatory and inhibitory currents converging onto single l2/3 pyramidal cells were measured in the s1 somatosensory cortex in acute slices. epsc amplitudes were compared at the minimum l4 stimulation intensity required to evoke a detectable epsc and at peak current amplitude.
Description: Mutants show smaller feedforward epsc amplitudes and decrease in area under mean epsc input-output curves compared with controls.
Exp Paradigm: L4-evoked feedforward excitatory and inhibitory currents converging onto single l2/3 pyramidal cells were measured in the s1 somatosensory cortex in acute slices. epsc amplitudes were compared at the minimum l4 stimulation intensity required to evoke a detectable epsc and at peak current amplitude.
Description: Mutants show decrease in ipscs compared with controls.
Exp Paradigm: L4-evoked feedforward excitatory and inhibitory currents converging onto single l2/3 pyramidal cells were measured in the s1 somatosensory cortex in acute slices. epsc amplitudes were compared at the minimum l4 stimulation intensity required to evoke a detectable epsc and at peak current amplitude.
Description: Increased susceptibility to sound-induced seizures indicated by sequential seizure response of wild running, tonic-clonic seizures, and respiratory arrest, leading to death
Exp Paradigm: Audiogenic seizure assay
Description: Mutants show reduced firing of l2/3 fast but not regular spiking units in the vrc in response to whisker deflections compared with controls, indicating feedforward inhibition is reduced in vivo. mutants show no change in the fraction of l2/l3 regular spiking units that were responsive to whisker stimulation compared with controls.
Exp Paradigm: Single unit fast and regular spikes were recorded in c1-2 and d1-2 whisker columns in the vrc (ventral retrosplenial cortex) with laminar polytrodes in l4 and l2/3 of s1 in adult urethane-anesthetized mice (p42-92). spiking was measured in response to calibrated whisker deflections.
Description: Mutants show decrease in firing of l2/l3 regular spiking units in response to whisker deflection in anesthetized juveniles and awake adults engaged in a visual detection task compared with controls. mutants show no change in the fraction of l2/l3 regular spiking units that were responsive to whisker stimulation compared with controls. mutants show no change in spike latency, jitter and tuning sharpness compared with controls. mutants show no change in firing rate of l4 regular spiking units in the vrc in response to whisker deflections compared with controls.
Exp Paradigm: Single unit regular spikes were recorded in c1-2 and d1-2 whisker columns in the vrc (ventral retrosplenial cortex) with laminar polytrodes in l4 and l2/3 of s1 in adult urethane-anesthetized mice. spiking was measured in response to calibrated whisker deflections. jitter is the standard deviation of spike times 4-50 ms post-stimulus, measured across all whiskers within a units whisker receptive field. tuning sharpness is the firing rate evoked by the bw (best whisker) divided by the sum of the bw-evoked firing rate plus mean firing rate to all immediately adjacent whiskers.
Description: Treatment with a pi3 k inhibitor construct instead of glua1 eliminates the benefits of treatment with the cocktail of 5ht and dopamine agonists and reduces cue conditioned choice learning to the level of fmr1 ko mice
Exp Paradigm: Y maze learning test was carried out using an elevated y maze, one start arma nd two goal arms. the food well located at the end of each goal arm was filled with sucrose sweetened non fat dairy milk as a reward. after 18 h food fasting with no restriction on water access, mice were first habituated to y maze and milk reward. mice were then trained and tested on a conditional learning task using interchangeable floor inserts, either plain or white or black wire mesh, covering the whole of the start arm, this was the conditional cue. the presence of the plain white insert indicated the presence of milk reward in the right goal arm and the black wire mesh indicated the milk reward was present in the left arm. mice received 14 training sessions consisting of 10
Description: Treatment with a pi3 k inhibitor eliminates the benefits of treatment with the cocktail of 5ht and dopamine agonists and reduces learning mediated freesing to the level of fmr1 ko mice
Exp Paradigm: Trace fear conditioning traning consisted of a 15-sec white noise conditioned stimulus (cs) and a 0.5 s scrambled foot shock (us). mice were acclimated for 60 sec and then presented with seven cs-trace-us intertrial interval trials ( trace, 30 sex, iti, 210 sec). one day after training, mice were acclimated for 60 sec followed by 7 cs iti trials ( iti, 30 sec) in a novel chamber to test for trace fear memory.
Description: Infecting with the dominant negative glua1 ct construct instead of glua1 eliminates the benefits of treatment with the cocktail of 5ht and dopamine agonists and reduces cue conditioned choice learning to the level of fmr1 ko mice
Exp Paradigm: Y maze learning test was carried out using an elevated y maze, one start arma nd two goal arms. the food well located at the end of each goal arm was filled with sucrose sweetened non fat dairy milk as a reward. after 18 h food fasting with no restriction on water access, mice were first habituated to y maze and milk reward. mice were then trained and tested on a conditional learning task using interchangeable floor inserts, either plain or white or black wire mesh, covering the whole of the start arm, this was the conditional cue. the presence of the plain white insert indicated the presence of milk reward in the right goal arm and the black wire mesh indicated the milk reward was present in the left arm. mice received 14 training sessions consisting of 10
Description: Infecting with the dominant negative glua1 ct construct instead of glua1 eliminates the benefits of treatment with the cocktail of 5ht and dopamine agonists and reduces learning mediated freezing to the level of fmr1 ko mice
Exp Paradigm: Trace fear conditioning traning consisted of a 15-sec white noise conditioned stimulus (cs) and a 0.5 s scrambled foot shock (us). mice were acclimated for 60 sec and then presented with seven cs-trace-us intertrial interval trials ( trace, 30 sex, iti, 210 sec). one day after training, mice were acclimated for 60 sec followed by 7 cs iti trials ( iti, 30 sec) in a novel chamber to test for trace fear memory.
Description: Syngap1 het: fmr1 null male double ko mice have a significant increase in the magnitidue of mglur dependent ltd in the hippocampus compared to wild type littermate controls and authors note the increase in magnitude is more than what is seen in the individual mutations (syngap1 het or fmr1-/y)
Exp Paradigm: NA
Description: Fmr1-sirna injected mice show decrease in time spent with an unfamiliar object over a familiar object compared with controls.
Exp Paradigm: NA
Description: Fmr1-sirna injected mice show decrease in fmr1 transcript in the dorsal striatum, 2 days after injection.
Exp Paradigm: Striatal tissue was used for qrt pcr.
Description: Mutants exhibited hairy skin hypersensitivity, measured by an increase of tactile prepulse inhibition of an acoustic startle response assay.
Exp Paradigm: NA
