Cell type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behaviour in fragile X syndrome model mice

Longo, Francesco; Aryal, Sameer; Anastasiades, Paul G.; Maltese, Marta; Baimel, Corey; Albanese, Federica; Tabor, Joanna; Zhu, Jeffrey; Oliveira, Mauricio M.; Gastaldo, Denise; Bagni, Claudia; Santini, Emanuela; Tritsch, Nicolas X.; Carter, Adam G.; Klann, Eric

doi:10.1101/2022.12.08.519509

Cited by 5 publications

(4 citation statements)

References 106 publications

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“…In contrast, Naaijen et al (2017) found no differences in striatal activity between autistic children and children with OCD, despite significantly greater compulsivity amongst autistic children. Several previous studies have also highlighted links between striatal activity and repetitive behavior, though much of this research has been conducted using animal models (e.g., Longo et al, 2022;Muehlmann et al, 2020). To better understand the links between neurological factors and manifestations of repetitive behavior, more studies assessing repetitive behaviors as a multidimensional construct are needed.…”

Section: Discussionmentioning

confidence: 99%

Repetitive Behaviors in Autism and Obsessive-Compulsive Disorder: A Systematic Review

O’Loghlen,

McKenzie,

Lang

et al. 2024

J Autism Dev Disord

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Purpose Obsessive-compulsive disorder (OCD) and autism are characterized by the presence of repetitive behaviors. Differentiating between repetitive behaviors attributable to a diagnosis of autism, and those attributable to OCD, poses challenges for differential and co-occurring diagnosis. Differentiation is important to inform appropriate supports and interventions for phenotypically similar but functionally distinct behaviors. In this systematic review, the quantitative literature was examined to explore the similarities and differences in repetitive behaviors (including restricted and repetitive behaviors and interests, and obsessive-compulsive behaviors) in autistic individuals and those with OCD, and those with co-occurring diagnoses, in terms of: (1) expression, (2) content, and (3) associated factors. Methods: Thirty-one studies were identified that compared repetitive behaviors in autistic individuals, individuals with OCD, or individuals with both diagnoses. Results: The results suggest considerable overlap in the intensity and content of repetitive behaviors between groups. The findings of this review highlight that research aimed specifically at understanding similarities and differences in repetitive behaviors between autistic individuals and individuals with OCD is limited and frequently only compare at total score or composite measure levels. Conclusion: Further research into differences in the presentation of repetitive behaviors at a subscale and item level is required to inform clearer differentiation of specific behaviors in autism versus OCD. Understanding and more accurately differentiating is essential for efficient diagnosis, effective treatment, and better outcomes.

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Section: Discussionmentioning

confidence: 99%

Repetitive Behaviors in Autism and Obsessive-Compulsive Disorder: A Systematic Review

O’Loghlen,

McKenzie,

Lang

et al. 2024

J Autism Dev Disord

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“…FXS is a genetic form of intellectual disability and ASD characterized by the genetic inactivation of Fmrp, encoding for an RNA-binding protein that represses the translation of a specific subset of mRNAs associated with eIF4E. Thus, FXS model mice exhibit increased eIF4E-dependent protein synthesis along with hyperactive mTOR signaling 83,84 . The dysregulated protein synthesis is accompanied by diminished evoked DA release detected by FSCV in acute corticostriatal slices 85 and behavioral inflexibility in a touchscreen operant task 86 .…”

Section: Discussionmentioning

confidence: 99%

Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders

Carbonell-Roig,

Aaltonen,

Cartocci

et al. 2024

Preprint

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Autism Spectrum Disorders (ASD) consist of diverse neurodevelopmental conditions where core behavioral symptoms are critical for diagnosis. Altered dopamine neurotransmission in the striatum has been suggested to contribute to the behavioral features of ASD. Here, we examine dopamine neurotransmission in a mouse model of ASD characterized by elevated expression of the eukaryotic initiation factor 4E (eIF4E), a key regulator of cap-dependent translation, using a comprehensive approach that encompasses genetics, behavior, synaptic physiology, and imaging. The results indicate that increased eIF4E expression leads to behavioral inflexibility and impaired striatal dopamine release. The loss of normal dopamine neurotransmission is due to a defective nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons. These findings reveal an intricate interplay between eIF4E, DA neurotransmission, and behavioral flexibility, provide a mechanistic understanding of ASD symptoms and offer a foundation for targeted therapeutic interventions.

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“…Acute PERK inhibition, although not tested in TSC mouse models, has been shown to improve cognitive function by boosting translation output 57,58 . On the other hand, chronic PERK inhibition is associated with impaired behavioral flexibility and working memory deficit 59,60 . Hence, we asked whether subchronic inhibition of either mTORC1 or PERK could rescue stress-precipitated anxiety in Tsc2 cHET males and social avoidance in cHET females.…”

Section: Mainmentioning

confidence: 99%

Aberrant TSC-Rheb axis in Oxytocin receptor+ cells mediate stress-induced anxiety

Tabaka,

Lawal,

Triana

et al. 2024

Preprint

Self Cite

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Stress is a major risk for the onset of several maladaptive processes including pathological anxiety, a diffuse state of heightened apprehension over anticipated threats1. Pathological anxiety is prevalent in up to 59% of patients with Tuberous Sclerosis complex (TSC)2, a neurodevelopmental disorder (NDD) caused by loss-of-function mutations in genes for Tuberin (Tsc2) and/or Hamartin (Tsc1) that together comprise the eponymous protein complex. Here, we generated cell type-specific heterozygous knockout ofTsc2in cells expressing oxytocin receptor (OTRCs) to model pathological anxiety-like behaviors observed in TSC patient population. The stress of prolonged social isolation induces a sustained negative affective state that precipitates behavioral avoidance, often by aberrant oxytocin signaling in the limbic forebrain3,4. In response to social isolation, there were striking sex differences in stress susceptibility in conditional heterozygote mice when encountering situations of approach-avoidance conflict. Socially isolated male mutants exhibited behavioral avoidance in anxiogenic environments and sought more social interaction for buffering of stress. In contrast, female mutants developed resilience during social isolation and approached anxiogenic environments, while devaluing social interaction. Systemic and medial prefrontal cortex (mPFC)-specific inhibition of downstream effector of TSC, the integrated stress response (ISR), rescued behavioral approach toward anxiogenic environments and conspecifics in male and female mutant mice respectively. Further, we found thatTsc2deletion in OTRCs leads to OTR-signaling elicited network suppression, i.e., hypofrontality, in male mPFC, which is relieved by inhibiting the ISR. Our findings present evidence in support of a sexually dimorphic role of prefrontal OTRCs in regulating emotional responses in anxiogenic environments, which goes awry in TSC. Our work has broader implications for developing effective treatments for subtypes of anxiety disorders that are characterized by cell-autonomous ISR and prefrontal network suppression.

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Cell type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behaviour in fragile X syndrome model mice

Cited by 5 publications

References 106 publications

Repetitive Behaviors in Autism and Obsessive-Compulsive Disorder: A Systematic Review

Repetitive Behaviors in Autism and Obsessive-Compulsive Disorder: A Systematic Review

Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders

Aberrant TSC-Rheb axis in Oxytocin receptor+ cells mediate stress-induced anxiety

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