Several studies have found a genetic association of the CNTNAP2 gene with autism. Among these, one study (Li et al., 2010) found positive association with the Chinese Han population. In addition, rare variants in the CNTNAP2 gene, including deletions and nonsynonymous changes, are also suggested to play a role in autism, ID, DD and language impairment. Interestingly, positive associations with CNTNAP2 and selective mutism, epilepsy and specific language impairment have also been found.
Molecular Function
This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein is localized at the juxtaparanodes of myelinated axons and associated with potassium channels.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism.
CNTNAP2 gene polymorphisms in autism spectrum disorder and language impairment among Bangladeshi children: a case-control study combined with a meta-analysis
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
CASPR2-Deficiency Neurodevelopmental Disorder Associated With Biallelic CNTNAP2 Gene Variants: Phenotypic and Genetic Analysis From Prenatal to Paediatric Period
592 ASD families (492 trios, 73 duos, 27 singletons) recruited at the Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy at JW Goethe University Frankfurt/Main and at Saarland University Hospital
592 ASD families (492 trios, 73 duos, 27 singletons) recruited at the Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy at JW Goethe University Frankfurt/Main and at Saarland University Hospital
67 children with autistic disorder (49 boys, 18 girls, aged 38-98 months) and 57 typically developing children (34 boys, 23 girls, aged 53-90 months) recruited from Kanazawa University and affiliated hospitals.
59 Japanese children with ASD (41 boys, 18 girls, age 40-98 months) and 57 typically-developing Japanese children (34 boys, 23 girls, age 53-90 months)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Gene targeted replacement of exon 1 of Cntnap2 gene with a oppositely directed neo gene.
Allele Type: Knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: 129S1/Sv * 129X1/SvJ * ICR
ES Cell Line: R1
Mutant ES Cell Line: Model Source: Peles lab
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Transgene of HA-tagged construct of human Cntnap2 cDNA with 4.1B binding domain deletion, C2d4.1 (delection of amino acids R1298 to H1304), in Cntnap2 knockout mice (PMID 12963709).
Allele Type: Humanized LOF mutation
Strain of Origin: CB6F1 (Transgene); (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: BALB/c * C57BL/6 * 129S1/Sv * 129X1/SvJ * ICR
ES Cell Line: Mutant ES Cell Line: Model Source: Peles lab
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Gene targeted replacement of exon 1 of Cntnap2 gene with an oppositely directed neo gene. In Gao et al. 2018 (PMID 29610457) Cntnap2 null mutant mice were crossed with heterozygous transgenic mice carrying the interneuron-specific Gad1-eGFP reporter to generate Cntnap2 null mutant (test animals) and wildtype (controls) mice with the reporter. In PMID 31853066 mice were inbred after colonizing with segmented filamentous bacteria (SFB) from donor mice.
Allele Type: Knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6J
ES Cell Line: R1
Mutant ES Cell Line: Model Source: Peles lab
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted replacement of exon 1 of Cntnap2 gene maintained as a heterozygous.
Allele Type: Knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6J
ES Cell Line: R1
Mutant ES Cell Line: Model Source: Peles lab
Model Type:
Multifactorial
Model Genotype:
Homozygous
Mutation:
Homozygous Cntnap2 KO mice are obtained by crossing heterozygous Cntnap2 KO mice and subjecting the pregnant females to a MIA at gestational day GD7 (0.30 mg/kg LPS in saline by subcutaneous injections).
Allele Type: Knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6J
ES Cell Line: R1
Mutant ES Cell Line: Model Source: Peles lab
Model Type:
Multifactorial
Model Genotype:
Homozygous
Mutation:
Homozygous Cntnap2 KO mice are obtained by crossing heterozygous Cntnap2 KO mice and subjecting the pregnant females to a MIA at gestational day GD7 (0.30 mg/kg LPS in saline by subcutaneous injections).
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Cntnap2^tlacz/ knockin allele abolishes contactin associated protein-like 2 gene function and instead expresses a tau-LacZ gene and a neo cassette from the Cntnap2 promoter/enhancer elements.
Allele Type: LOF Knockin
Strain of Origin: Genetic Background: C57BL/6J*129/SvEv*CD1
ES Cell Line: Mutant ES Cell Line: Model Source: Peles lab
Model Type:
Genetic LOF
Model Genotype:
Wildtype
Mutation:
Knockdown of cntnap2 in layer 2/3 pyramidal neurons of the developing mouse prefrontal cortex. pregnant icr mice at e14â??15 were injected intraperitoneally with egfp-pcag plasmid vectors carrying rnai to knockdown the expression of cntnap2 pyramidal neurons.
Allele Type: Wildtype
Strain of Origin: ICR
Genetic Background: ICR
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Multifactorial
Model Genotype:
Homozygous
Mutation:
Gene targeted replacement of exon 1 of cntnap2 gene with an oppositely directed neo gene identical to model m_cntnap2_5_ko_hm. control wt c57bl/6j (stock #000664) and cntnap2 ko hm (cntnap2tm1pele, stock # 017482) (poliak et al., 2003) were obtained from jackson
Allele Type: Knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6J
ES Cell Line: R1
Mutant ES Cell Line: R1
Model Source: C57BL/6J
Model Type:
RESCUE-Microbiome
Model Genotype:
Homozygous
Mutation:
L. reuteri was added to the drinking water daily to minimize dosage variability. the experimental group received live bacteria (approximately 10^8 organisms/mouse/day), while the control group received equal volume of pbs. mice drank the treated water ad libitum during the treatment period. fecal sample collection, behavioral assays, tissue collection and electrophysiological recordings were initiated 4 weeks after the beginning of the treatment period.
Allele Type: Knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6JÂ
ES Cell Line: R1
Mutant ES Cell Line: R1
Model Source: C57BL/6JÂ
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Gene targeted replacement of exon 1 of Cntnap2 gene with a oppositely directed neo gene. A subset of mice were homozygous for Cntnap2 KO and heterozygous for Oxt-Cre (obtained from JAX, #024234) for DREADD experiments targetted to PVN OXT neurons using AAV-OXT-hM3D(Gq)-mCherry or AAVhSyn-DIO-hM3D(Gq)-mCherry; M_CNTNAP2_1_KO_HM crossed to C57BL/6J background for 12 generations
Allele Type: Knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: 129S1/Sv * 129X1/SvJ * ICR * C57BL/6J
ES Cell Line: R1
Mutant ES Cell Line: Model Source: Peles lab
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Cntnap2^I1254T knock-in mice were generated using CRISPRâ??Cas9-mediated gene targeting. The targeted missense mutation changes an ATA DNA sequence to ACG in exon 23, which results in an isoleucine to threonine amino acid change in the CNTNAP2 protein. The I1254T mutation in the CNTNAP2 protein corresponds to the pathogenic I1253T mutation in ASD patients. Heterozygous mice carry one copy of the mutant allele.
Allele Type: ASD mutation
Strain of Origin: Not specified
Genetic Background: Not specified
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source: Weihong Song
Description: Abnormal expression of protein 4.1 b in sciatic nerve fibers with reduced expression in nodes, and normal expression at the paranodal junctions (pnj), justaparanodal region (jxp), and the internodes
Exp Paradigm: Protein 4.1b expression
Description: Decreased expression of kv1.2 channels and tag-1 at the juxtaparanodal region in sciatic nerves
Exp Paradigm: Juxtaparanodal region protein expression
Circadian rhythms: timing/phases of locomotor activity2
Abnormal
Description: Decreased activity of knockout mice in the transitions between light and dark phases. core body temperature was reduced in knockout mice at all transitions.
Exp Paradigm: Mice were implanted with f20-eet transmitters for recording eeg, emg, locomotor activity and core body temperature at 3 months, and given 2 weeks to recover. 24-h recording was collected. locomotor and core body temperature were collected in 10-s increments.- body temperature measurement
Description: Knockout mice exhibited relatively normal time in all vigilance states. for each state, the time spent during the 24-h period and each light/dark phase was normal. the time knockout mice spent in wake was fragmented during the dark phase since they had more wake bouts.
Exp Paradigm: Mice were implanted with f20-eet transmitters for recording eeg, emg, locomotor activity and core body temperature at 3 months, and given 2 weeks to recover. 24-h recording was collected. eeg and emg recordings were sampled at 500 hz with filter cutoffs at 200 hz (eeg) and 100 hz (emg).
Description: Sleep architecture of knockout mice was relatively normal, with rem bouts being of shorter duration only during the dark phase. latency to enter both rem and nrem sleep was shorter in knockout mice.
Exp Paradigm: Mice were implanted with f20-eet transmitters for recording eeg, emg, locomotor activity and core body temperature at 3 months, and given 2 weeks to recover. 24-h recording was collected. eeg and emg recordings were sampled at 500 hz with filter cutoffs at 200 hz (eeg) and 100 hz (emg).
Circadian rhythms: timing/phases of locomotor activity2
Abnormal
Description: Decreased activity of knockout mice in the transitions between light and dark phases. core body temperature was reduced in knockout mice at all transitions.
Exp Paradigm: Mice were implanted with f20-eet transmitters for recording eeg, emg, locomotor activity and core body temperature at 3 months, and given 2 weeks to recover. 24-h recording was collected. locomotor and core body temperature were collected in 10-s increments.-electromyogram (emg): home cage
Description: Mutants show increased velocity of locomotion during social interaction bouts compared to controls.
Exp Paradigm: The test duration was 10 minutes.
Description: Significant differences overall, particularly in gait, paw image, and paw position; no difference in length of stride; durations of the stride and stance were slightly reduced at p60
Exp Paradigm: Only males tested; neurocube system measured gait geometry and dynamics, body motion, through neurocube analysis, paw image intensity, paw area, paw position, length of stride, duration of stride, duration of stance, width of hindbase (increased), time in swing phase, rhythm of gait, pivoting, rearing, spead of gait-footprint analysis
Description: Significant differences overall, particularly in gait, paw image, and paw position; no difference in length of stride; durations of the stride and stance were slightly reduced at p60
Exp Paradigm: Only males tested; neurocube system measured gait geometry and dynamics, body motion, through neurocube analysis, paw image intensity, paw area, paw position, length of stride, duration of stride, duration of stance, width of hindbase (increased), time in swing phase, rhythm of gait, pivoting, rearing, spead of gait- running stride analysis
Description: Discrimination values between the cntnap2 wt and homozygous mice reached 88%
Exp Paradigm: Only males tested; measured general restlessness, freezing time, latency to approach aversive stimuli, abrupt movement, locomotion bouts, freezing time, latency to approach aversive stimuli: difference between distributions of discrimination indexes is used to estimate probability of null hypothesis
Description: Abnormal neuronal migration indicated by presence of ectopic neurons in corpus callosum
Exp Paradigm: Neun immunohistochemistry in brain slices
Description: Abnormal neuronal migration indicated by abnormal laminar positioning of upper cortical layer cells in deep cortical layers
Exp Paradigm: Immunohistochemical analysis using anti-cux1 and anti-foxp2 antibodies for upper-cortical layers &
Description: Cntnap2 mutant mice exhibited decreased expression of NR1, Synaptophysin, GAD1, and VGAT in the cortex and striatum compared to wildtype control mice. Mutant mice exhibited no change in expression of Homer and PSD95 in the cortex and striatum compared to wildtype control mice.
Exp Paradigm: cortex, striatum
Dendritic architecture: dendritic tree complexity9
Decreased
Description: Mutants show decreased dendritic complexity of interneurons in the layer iv/v interneurons compared to controls, measured by dendritic intersections within 125 micrometer from the soma.
Exp Paradigm: Analysis was focused on cingulate cortex/m2 areas.
Description: Cntnap2 ko mice have significantly reduced number of oxytocin expressing (+ve) neurons in the paraventricular nucleus of the hypothalamus by p30.
Exp Paradigm: NA
Description: Abnormal distribution of cells with shortage of cells in upper cortical layers
Exp Paradigm: Brdu neuron birthdaying of sections of e16.5-labeled mice
Description: Mutants show decreased dendritic length of interneurons in the layer iv/v interneurons compared to controls.
Exp Paradigm: Analysis was focused on cingulate cortex/m2 areas.
Description: Decreased number of gabaergic interneurons in all laminae with largest decrease in pvalb+ interneurons; decrease in striatal gabaergic interneurons and pvalb+ interneurons in hippocampus
Exp Paradigm: Gad1, pv, clr, npy
Functional magnetic resonance imaging: connectivity15
Increased
Description: Voxelwise rsfMRI connectivity mapping of S1 revealed increased functional connectivity within somatosensory cortex in Cntnap2 null mice. Unilateral quantifications of rsfMRI signal in regions of interest confirmed functional over-connectivity within the right and left somatosensory cortex (S1), but no change in ventral posterior medial thalamic nucleus VPM-control region.
Functional magnetic resonance imaging (FMRI)-resting state
Description: Mutants show disruptions in neuronal activity along the corticostriatal projections compared to controls.
Exp Paradigm: Local neural circuit activity was quantified in freely moving mice using fiber photometry. a ca2+ indicator that change fluorescence properties during neuronal firing was genetically inserted in pv neurons of the mpfc.
Description: Mutants show increased neural activity in the parvalbumin neurons of the medial prefrontal cortex upon social interaction with a novel object compared to controls. mutants show similar levels of pv neural activity when mice are engaged in novel social interactions or novel object interactions whereas control pv neuron activity was higher during novel (non-familiar) social interactions compared to novel object interactions.
Exp Paradigm: Local neural circuit activity was quantified in freely moving mice using fiber photometry. a ca2+ indicator that change fluorescence properties during neuronal firing was genetically inserted in pv neurons of the mpfc.
Description: Mutants show decrease in peak amplitude of postsynaptic potential but no change in the number of spikes following a train of l4 stimulation compared with controls indicating no change in temporal summation.
Exp Paradigm: L4 train-evoked postsynaptic potentials and spikes in l2/3 pyramidal cells (5 pulses at 20 hz).
Neuronal activation: non-familiar social interaction8
Increased
Description: Mutants show increased neural activity in the parvalbumin neurons of the medial prefrontal cortex upon social interaction with a non-familiar conspecific compared to controls. mutants show similar levels of pv neural activity when mice are engaged in novel social interactions or novel object interactions whereas control pv neuron activity was higher during novel (non-familiar) social interactions compared to novel object interactions. mutants show increased pv neuronal activity when engaged in social interaction with a non-familiar mouse than with a familiar mouse whereas control mice show no difference in pv neuronal activity when engaged in social interaction with a familiar or non-familiar mouse.
Exp Paradigm: Local neural circuit activity was quantified in freely moving mice using fiber photometry. a ca2+ indicator that change fluorescence properties during neuronal firing was genetically inserted in pv neurons of the mpfc.
Description: Abnormal firing indicated by highly asyncrhonous pattern with lower mean correlation coefficient of firing time between connected neurons
Exp Paradigm: In vivo two-photon calcium imaging of layer ii/iii neurons from somatosensory cortex
Description: Cntnap2 mutant mice exhibited increased 3-Nitrotyrosine protein expression in the cortex and striatum compared to wildtype controls.
Exp Paradigm: cortex, striatum
Description: Mutants show increased neural activity in the parvalbumin neurons of the medial prefrontal cortex upon social interaction with a familiar conspecific compared to controls.
Exp Paradigm: Local neural circuit activity was quantified in freely moving mice using fiber photometry. a ca2+ indicator that change fluorescence properties during neuronal firing was genetically inserted in pv neurons of the mpfc.
Description: Increased perseveration indicative of decreased cognitive flexibility demonstrated by no alternations
Exp Paradigm: Spontaneous alternation t maze test
Description: Knockout mice self-groomed longer than wildtype mice during a self-grooming test.
Exp Paradigm: Each mouse was placed in a clean cage (29 x 18 x 13 cm) with a clear lid and habituated for 5 min before starting the 10 min test. grooming events were recorded with an overhead camera.
Description: Knockout mice exhibited a significant increase in the frequency of seizure-like spiking events during eeg recordings.
Exp Paradigm: Mice were implanted with f20-eet transmitters for recording eeg, emg, locomotor activity and core body temperature at 3 months, and given 2 weeks to recover. 24-h recording was collected. eeg and emg recordings were sampled at 500 hz with filter cutoffs at 200 hz (eeg) and 100 hz (emg).
Description: Cntnap2 null mice show increased neuronal activation following whisker stimulation somatosensory S1 cortex, by quantification of c-fos mRNA, with similar patterns of induction in somatosensory S1 layers L2/3, L4 and L5/6, but no change in induction in other regions (motor cortex, medial thalamic nuclei, amygdala).
Description: During learning phase, both genotypes did not show any preference for one of the identical textured objects. During test phase, control mice spent a significantly larger amount of time exploring the novel object, Cntnap2 null mice spent comparable time exploring the novel and the familiar object.
Description: Decreased juvenile play behavior indicated by less time interacting with novel mouse and increased grooming and digging
Exp Paradigm: Juvenile play test
Description: Decreased responsiveness to social odors and degrees of habituation and dishabituation behavior after sequential exposure to these odors
Exp Paradigm: NA
Description: Mutants explore conspecific mice for shorter durations compared to controls. mutants interact with novel conspecifics for shorter durations than controls. in mutants average duration of interaction with a novel object or familiar littermates did not differ compared to controls.
Exp Paradigm: The test duration was 10 minutes.
Description: Cntnap2 ko mice spend significantly less time interacting with a age,sex-matched stimulus mouse in the reciprocal social interaction test that wild type control mice
Exp Paradigm: NA
Description: Cntnap2 mutant male mice displayed decreased sociability, showing no preference for either the stranger mouse or empty cage, while wildtype male mice spent significantly more time interacting with the stranger mouse than with the empty cage. Cntnap2 mutant female mice displayed no preference for either the stranger mouse or the empty cage, similar to wildtype female controls.
Exp Paradigm: First session: mice encounter a stranger mouse (S) and an empty cage (E).
Description: Knockout mice spent less time socially interacting with same-genotype partners.
Exp Paradigm: Mice were isolated 24 h prior to testing. each mouse pair was placed in a clear box (40.5 x 18.5 x 22 cm). behavior was video recorded for 10 min with an overhead camera. each animal was scored for non-social and social behaviors. play behaviors include: pouncing, pinning, wrestling, chasing, play grooming.
Digestive system function: gastrointestinal motility: peristaltic reflexes14
Decreased
Description: Cntnap2 knockout mice show 31% shorter-lasting colonic motor complexes (CMCs) compared to wildtype mice. CMC intervals, number, velocity, and length remained unchanged. Thus, repetitive contractions are shortened in isolated empty Cntnap2 mutant colons.
In vitro analysis of colonic migrating motor complexes (CMMCs)
Digestive system function: gastrointestinal motility: colonic motility14
Increased
Description: Cntnap2 knockout mice show shortened time to pellet expulsion (51%) compared to Cntnap2 wildtype littermate controls. Cntnap2 knockout mice show a 42% reduction in the number of pellet movements.
Digestive system function: gastrointestinal motility: colonic motility14
Increased
Description: Cntnap2 knockout mice show a shortened interval between CMC onsets (47%) compared to wildtype mice, while the number of CMCs per trial remained the same. As a result, Cntnap2 knockout mice show an increase of 73% in CMC frequency. CMC velocity, length, and duration remained the same.
In vitro analysis of colonic migrating motor complexes (CMMCs)
Description: Decreased isolation-induced ultrasonic vocalizations in the cntnap2 ko mice regardless of sex
Exp Paradigm: Monitoring ultrasonic vocalizations
Ultrasonic vocalization: interaction induced: opposite sex stimulus6
Decreased
Description: Male cntnap2 mutants vocalizations were reduced compared to wt controls in response to the stimulus of female urine in the open field chamber
Exp Paradigm: NA
Description: Adult but not neonate m_cntnap2_5_ko_hm mice gained weight at a slightly lower rate than wt mice, and were significantly lighter than wt mice at p90
Exp Paradigm: Only males tested
Description: Significantly more mutant pups rolled on their side than controls
Exp Paradigm: Scored in male pups only; test pup placed in a plexiglas chamber atop a laminated grid-paper for a 2 minute observation
Description: Fewer pups had eyes open at p13
Exp Paradigm: Only males tested; eyes were scored at p13 as closed(0), half open(0.5) and open (1). scores for each eye summated per mouse.
Description: Knockout mice weighed consistently less that wildtype controls (never exceeding 10% that of wild-type mice)
Exp Paradigm: Body weight measurement
Description: At p15, mutant mice walked down more than controls
Exp Paradigm: Only males tested; mice were placed on an inclined plane and their behavior observed; scored percent falls, turns, walk downs or no reaction
Description: Cntnap2 mutant male mice spent significantly more time in the closed arms compared to wildtype male controls. Cntnap2 mutant female mice spent significantly less time in the open arms and significantly more time in the closed arms compared to wildtype female mice.
Description: Knockout mice showed increased exploratory activity in the open field test for the first 15 min, and their activity normalized by the last 5 min.
Exp Paradigm: Mice were placed in a clear acrylic arena (40 x 40 x 30 cm) and activity was recorded for 20 min. the light intensity was 20 lux.
Description: Cntnap2 mutant mice did not explore the chambers containing the stimuli as much as wt controls
Exp Paradigm: Only males tested; limelight tracking software
Description: Increased reactive astrocytosis indicated by enhanced expression of glial fibrillary acidic protein (gfap) throughout hippocampus with no neuronal loss
Exp Paradigm: Western blot analysis using anti-gfap antibodies and anti-neun to quantify neuronal loss
Description: Decreased cognitive flexibility demonstrated by impariment in learning new location
Exp Paradigm: Classic reversal task of morris water maze
Description: Acquisition of spatial memory was faster in mutants
Exp Paradigm: Only males tested; criteria set at 6 out of 8 correct trials in two consecutive days
Description: Wildtype mice spent significantly more time exploring the novel object than the familiar object, whereas Cntnap mutant mice did not exhibit any significant preference for the novel object over the familiar one.
Description: Learning of the conditioned response is significantly reduced in cntnap2 null mice but the reponse amplitude is not affected
Exp Paradigm: Males only
Description: Cntnap2 mutant mice exhibited decreased expression of Cntnap2 protein in the cortex compared to wildtype control mice.
Exp Paradigm: cortex
Description: Mutants show a slight but significant reduction in cask protein levels in the membrane fraction of cortical homogenates compared to controls.
Exp Paradigm: Analysis was focused on cingulate cortex/m2 areas.
Description: Decreased h3 trimethylation on lysine 27 (h3k27me3, a repressive mark) at the promoter area of crhr1 in the hippocampus of female cntnap2 ko mice relative to female wildtype controls
Exp Paradigm: Chromatin immunoprecipitation (chip); quantitative pcr (qrt-pcr): crhr1 promoter
Description: Mutants show no cntnap2 in mouse whole cortical homogenates or in the membrane fraction of whole cortical homogenates compared to controls.
Exp Paradigm: Analysis was focused on cingulate cortex/m2 areas.
Spontaneous post synaptic event frequency: inhibitory currents4
Decreased
Description: Mutants show reduced spontaneous mipsc frequency in l2/l3 pyramidal neurons of the s1 somatosensory cortex compared with controls.
Exp Paradigm: S1 somatosensory cortex; acute slices; l2/3 pyramidal neurons
Spontaneous post synaptic event frequency: excitatory currents4
Decreased
Description: Mutants show reduced spontaneous mepsc frequency in l2/l3 pyramidal neurons of the s1 somatosensory cortex compared with controls.
Exp Paradigm: S1 somatosensory cortex; acute slices; l2/3 pyramidal neurons
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: 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 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. mutants show no change in spike latency, jitter and tuning sharpness compared with controls. mutants show decrease in the firing rate of l4 regular spiking units in the vrc compared with controls.
Exp Paradigm: Single unit regular spikes were recorded in c1-2 and d1-2 whisker columns in the vrc (ventral retroslenial 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: Mia induced male cntnap2 ko mice exhibit increased locomotor activity relative to no-mia female wildtype controls
Exp Paradigm: Open field test
Description: Decreased expression of crhr1 (corticotropin releasing hormone receptor 1) in the left hippocampus of the mia induced male cntnap2 ko mice relative to no-mia female wildtype controls
Exp Paradigm: Quantitative pcr (qrt-pcr)
Description: Decreased social dishabituation in the mia induced male cntnap2 ko mice relative to no-mia female wildtype controls
Exp Paradigm: Social recognition test
Description: Decreased social habituation in the mia induced male cntnap2 ko mice relative to no-mia female wildtype controls
Exp Paradigm: Social recognition test
Description: Decreased isolation-induced ultrasonic vocalizations in the mia induced male cntnap2 ko mice relative to no-mia female wildtype controls
Exp Paradigm: Monitoring ultrasonic vocalizations
Description: Decreased h3 trimethylation on lysine 4 (h3k4me3) at the promoter area of crhr1 in the left hippocampus of the mia induced male cntnap2 ko mice relative to no-mia female wildtype controls
Exp Paradigm: Chromatin immunoprecipitation (chip); quantitative pcr (qrt-pcr): crhr1 promoter
Description: Mutants exhibited hairy skin hypersensitivity, measured by an increase of tactile prepulse inhibition of an acoustic startle response assay.
Exp Paradigm: NA
Description: Egfp positive transfected cells with cntnap2 knockdown at postnatal 8â??18 weeks were layer 2/3 pyramidal neurons were located in the pfc, including the dorsolateral prefrontal cortex (dl-pfc), medial prefrontal cortex (mpfc), orbitofrontal cortex (ofc), and anterior cingulate cortex (cgcx)
Description: Metabolomic profile of mutant mice is markedly different ; top two most discriminatory metabolites between the socially normal and deficient mice were biopterin and dihydrobiopterin
Description: Increased speed of locomotion assessed in the habituation phase of the 3-chamber test; spri3 did not affect the locomotor activity of l. reuteri treated mutants
Description: Increased speed of locomotion assessed in the habituation phase of the 3-chamber test; spri3 did not affect the locomotor activity of l. reuteri treated mutants
Miniature post synaptic current amplitude: excitatory1
Refractory
Description: Failed to reverse decrease in mepsc amplitude, indicating l. reuteri modulates changes in synaptic transmission selectively in the vta but not in the mpfc
Miniature post synaptic current frequency: excitatory1
Refractory
Description: Failed to reverse decrease in mepsc frequency, indicating l. reuteri modulates changes in synaptic transmission selectively in the vta but not in the mpfc
Description: No change in time spent with unfamiliar mouse over object; when bh4 synthesis was pharmacologically blocked, l. reuteri failed to rescue the social deficits in mutants
Description: No change in time spent with unfamiliar mouse over familiar mouse; when bh4 synthesis was pharmacologically blocked, l. reuteri failed to rescue the social deficits in mutants
Description: No change in time spent with unfamiliar mouse; when bh4 synthesis was pharmacologically blocked, l. reuteri failed to rescue the social deficits in mutants
Description: L. reuteri did not shift the overall metabolomic profile of the mutant mice back to a wildtype state; l. reuteri promotes the level of metabolites in the bh4 pathway
Functional magnetic resonance imaging: connectivity1
abnormal
Description: Cntnap2 KO mice showed macroscale differences in resting state functional connectivity between 7 brain regions, with the highest aberrant connections in the forebrain nuclei; when focusing on social ROI, KO mice showed decreased resting state functional connectivity within these regions but increased between these regions and other areas of the brain .
Functional magnetic resonance imaging (FMRI)-resting state
Description: OXT had an increased stimulation effect on Cntnap2 KO mice brains compared to WT injected with saline; increased number of c-Fos+ cells in nucleus accumbens, bed nucleus of stria terminalis, anterior insula, somatosensory cortex, visual cortex, and temporal association area; isocortex, hippocampus, and thalamus regions were significantly activated in the Cntnap2 KO compared to WT.
Exp Paradigm: c-Fos lightsheet imaging in iDISCO+-cleared brains
Description: OXT administration robustly increased the relative BOLD signal amplitude across numerous brain regions in Cntnap2 KO mice compared to saline in WT; activation was detected in the lateral and medial hypothalamus, bed nucleus of stria terminalis, dorsal peduncular area, and other cortical and subcortical regions (somatosensory, motor, retrospenial, hippocampus, thalamus, ventral tegmental area); BOLD signal increases were significantly related to the density of central OXT projections but not to density of brain-wide OXTR expression in WT mice
Exp Paradigm: OXT (Sigma, 1 mg/kg i.p. at 1 mg/mL) or saline of the same volume was administered via a catheter
Functional magnetic resonance imaging (FMRI)-resting state
Description: nucleus accumbens in Cntnap2 KO mice showed a significant DREADD-mediated increase in the number of c-Fos+ cells
Exp Paradigm: DREADD targeted to PVN OXT neurons (AAV-OXT-hM3D(Gq)-mCherry or AAVhSyn-DIO-hM3D(Gq)-mCherry in heterozygous Oxt-Cre mice)
