scholarly journals Effects of a postnatal Atrx conditional knockout in neurons on autism-like behaviours in male and female mice

2020 ◽  
Author(s):  
Nicole Martin-Kenny ◽  
Nathalie G. Bérubé
Keyword(s):  
Repeated Measures ◽  
Susceptibility Gene ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Autism Spectrum ◽  
Conditional Knockout ◽  
Male And Female ◽  
Female Mice ◽  
Excitatory Neurons ◽  
Behavioural Tests

AbstractBackgroundAlpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in excitatory neurons of the forebrain and performed a battery of behavioural assays that assess autistic-like behaviours.MethodsMale and female mice with a postnatal conditional knockout of Atrx were tested in a battery of behavioural tests that assess autistic features. We utilized paradigms that measure social behaviour, repetitive and stereotyped behaviours, as well as sensory gating. Statistics were calculated by two-way repeated measures ANOVA with Sidak’s multiple comparison test or unpaired Student’s T-tests as indicated.ResultsThe behaviour tests revealed no significant differences between Atrx-cKO and control mice. We identified sexually dimorphic changes in odor habituation and discrimination; however, these changes did not correlate with social deficits. We additionally observed sex-specific differences in sociability, vertical episodes, and acoustic startle response when results were analyzed by sex.ConclusionThe postnatal knockout of Atrx in forebrain excitatory neurons does not lead to autism-related behaviours in male or female mice.

scholarly journals Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Xiangling Meng ◽  
Wei Wang ◽  
Hui Lu ◽  
Ling-jie He ◽  
Wu Chen ◽  
...  
Keyword(s):  
Mouse Models ◽  
Neurological Disorders ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Loss Of Function ◽  
Glutamatergic Neurons ◽  
Excitatory Neurotransmission ◽  
Spectrum Disorders

Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-function mutations in MECP2, display impaired excitatory neurotransmission, the RTT phenotype can be largely reproduced in mice simply by removing MeCP2 from inhibitory GABAergic neurons. To determine what role excitatory signaling impairment might play in RTT pathogenesis, we generated conditional mouse models with Mecp2 either removed from or expressed solely in glutamatergic neurons. MeCP2 deficiency in glutamatergic neurons leads to early lethality, obesity, tremor, altered anxiety-like behaviors, and impaired acoustic startle response, which is distinct from the phenotype of mice lacking MeCP2 only in inhibitory neurons. These findings reveal a role for excitatory signaling impairment in specific neurobehavioral abnormalities shared by RTT and other postnatal neurological disorders.

P3-7. Neurophysiological profile of acoustic startle response in Japanese children with autism spectrum disorders

2013 ◽  
Vol 124 (8) ◽  
pp. e37-e38
Author(s):  
Hidetoshi Takahashi ◽  
Takayuki Nakahachi ◽  
Aiko Moriwaki ◽  
Reiko Takei ◽  
Yukako Iida ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Startle Response ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Japanese Children ◽  
Spectrum Disorders

scholarly journals Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission

2021 ◽  
Vol 118 (5) ◽  
pp. e2020705118
Author(s):  
Danilo De Gregorio ◽  
Jelena Popic ◽  
Justine P. Enns ◽  
Antonio Inserra ◽  
Agnieszka Skalecka ◽  
...  
Keyword(s):  
Social Behavior ◽  
Ampa Receptors ◽  
Knockout Mice ◽  
Autism Spectrum ◽  
Lysergic Acid ◽  
Conditional Knockout ◽  
Lysergic Acid Diethylamide ◽  
Excitatory Neurons ◽  
Synaptic Responses

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptorf/f:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptorf/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

scholarly journals Glucocorticoid Receptor Antagonist Mifepristone Does Not Alter Innate Anxiety-Like Behavior in Genetically-Selected Marchigian Sardinian (msP) Rats

2021 ◽  
Vol 22 (6) ◽  
pp. 3095
Author(s):  
Valentina Vozella ◽  
Bryan Cruz ◽  
Luis A. Natividad ◽  
Federica Benvenuti ◽  
Nazzareno Cannella ◽  
...  
Keyword(s):  
Sleep Disturbances ◽  
Glucocorticoid Receptors ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Stress Sensitivity ◽  
Acute Administration ◽  
Male And Female ◽  
Glucocorticoid Signaling ◽  
Candidate Target ◽  
Stress Coping Strategies

Marchigian Sardinian alcohol-preferring (msP) rats serve as a unique model of heightened alcohol preference and anxiety disorders. Their innate enhanced stress and poor stress-coping strategies are driven by a genetic polymorphism of the corticotropin-releasing factor receptor 1 (CRF1) in brain areas involved in glucocorticoid signaling. The activation of glucocorticoid receptors (GRs) regulates the stress response, making GRs a candidate target to treat stress and anxiety. Here, we examined whether mifepristone, a GR antagonist known to reduce alcohol drinking in dependent rats, decreases innate symptoms of anxiety in msPs. Male and female msPs were compared to non-selected Wistar counterparts across three separate behavioral tests. We assessed anxiety-like behavior via the novelty-induced hypophagia (NIH) assay. Since sleep disturbances and hyperarousal are common features of stress-related disorders, we measured sleeping patterns using the comprehensive lab monitoring system (CLAMS) and stress sensitivity using acoustic startle measures. Rats received an acute administration of vehicle or mifepristone (60 mg/kg) 90 min prior to testing on NIH, acoustic startle response, and CLAMS. Our results revealed that both male and female msPs display greater anxiety-like behaviors as well as enhanced acoustic startle responses compared to Wistar counterparts. Male msPs also displayed reduced sleeping bout duration versus Wistars, and female msPs displayed greater acoustic startle responses versus male msPs. Importantly, the enhanced anxiety-like behavior and startle responses were not reduced by mifepristone. Together, these findings suggest that increased expression of stress-related behaviors in msPs are not solely mediated by acute activation of GRs.

scholarly journals Relationship between physiological and parent-observed auditory over-responsiveness in children with typical development and those with autism spectrum disorders

Autism ◽  
2016 ◽  
Vol 22 (3) ◽  
pp. 291-298 ◽  
Author(s):  
Hidetoshi Takahashi ◽  
Takayuki Nakahachi ◽  
Andrew Stickley ◽  
Makoto Ishitobi ◽  
Yoko Kamio
Keyword(s):  
Autism Spectrum Disorders ◽  
Sensory Processing ◽  
Startle Response ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Autism Spectrum ◽  
Sensory Profile ◽  
Typical Development ◽  
Response Measures ◽  
Spectrum Disorders

The objective of this study was to investigate relationships between caregiver-reported sensory processing abnormalities, and the physiological index of auditory over-responsiveness evaluated using acoustic startle response measures, in children with autism spectrum disorders and typical development. Mean acoustic startle response magnitudes in response to 65–105 dB stimuli, in increments of 10 dB, were analyzed in children with autism spectrum disorders and with typical development. Average peak startle latency was also examined. We examined the relationship of these acoustic startle response measures to parent-reported behavioral sensory processing patterns in everyday situations, assessed using the Sensory Profile for all participants. Low-threshold scores on the Sensory Profile auditory section were related to acoustic startle response magnitudes at 75 and 85 dB, but not to the lower intensities of 65 dB. The peak startle latency and acoustic startle response magnitudes at low-stimuli intensities of 65 and 75 dB were significantly related to the low-threshold quadrants (sensory sensitivity and sensation avoiding) scores and to the high-threshold quadrant of sensation seeking. Our results suggest that physiological assessment provides further information regarding auditory over-responsiveness to less-intense stimuli and its relationship to caregiver-observed sensory processing abnormalities in everyday situations.

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