Cell-type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behavior 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:10.1016/j.celrep.2023.112901

Cited by 4 publications

(3 citation statements)

References 108 publications

(172 reference statements)

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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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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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“…Moreover, these compounds have been observed to normalize enhanced protein synthesis and mGluR-mediated LTD in the hippocampus in a Fragile X syndrome mouse model ( Thomson et al, 2017 ). Indeed, behavior abnormalities including RRB, excessive grooming and altered LTD, are rescued in this mouse model by administration of VU0152100, a positive allosteric modulator of MR4 ( Longo et al, 2023 ).…”

Section: Cellular and Molecular Mechanisms Of Repetitive Behaviormentioning

confidence: 95%

“…Furthermore, cell-type specific alterations have been taken into account in the Fmr1 KO mouse, a model of FXS characterized by RRB, marble-burying, nestlet shredding tests and self-grooming behavior. Longo and colleagues report dysregulated de novo protein synthesis specifically in dSPNs, due to an increased de novo cap-dependent translation ( Longo et al, 2023 ). Moreover, they find increased spine density in dSPNs of the DLS in the Fmr1KO mouse while no changes are detected in iSPNs.…”

Section: Cellular and Molecular Mechanisms Of Repetitive Behaviormentioning

confidence: 99%

Striatal insights: a cellular and molecular perspective on repetitive behaviors in pathology

Burton,

Longaretti,

Zlatanovic

et al. 2024

Front. Cell. Neurosci.

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Animals often behave repetitively and predictably. These repetitive behaviors can have a component that is learned and ingrained as habits, which can be evolutionarily advantageous as they reduce cognitive load and the expenditure of attentional resources. Repetitive behaviors can also be conscious and deliberate, and may occur in the absence of habit formation, typically when they are a feature of normal development in children, or neuropsychiatric disorders. They can be considered pathological when they interfere with social relationships and daily activities. For instance, people affected by obsessive-compulsive disorder, autism spectrum disorder, Huntington’s disease and Gilles de la Tourette syndrome can display a wide range of symptoms like compulsive, stereotyped and ritualistic behaviors. The striatum nucleus of the basal ganglia is proposed to act as a master regulator of these repetitive behaviors through its circuit connections with sensorimotor, associative, and limbic areas of the cortex. However, the precise mechanisms within the striatum, detailing its compartmental organization, cellular specificity, and the intricacies of its downstream connections, remain an area of active research. In this review, we summarize evidence across multiple scales, including circuit-level, cellular, and molecular dimensions, to elucidate the striatal mechanisms underpinning repetitive behaviors and offer perspectives on the implicated disorders. We consider the close relationship between behavioral output and transcriptional changes, and thereby structural and circuit alterations, including those occurring through epigenetic processes.

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ErbB inhibition rescues nigral dopamine neuron hyperactivity and repetitive behaviors in a mouse model of fragile X syndrome

D’Addario,

Rosina,

Massaro Cenere

et al. 2024

Preprint

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Repetitive behaviors are core symptoms of autism spectrum disorders (ASD) and fragile X syndrome (FXS), the prevalent genetic cause of intellectual disability and autism. The nigrostriatal dopamine (DA) circuit rules movement and habit formation; therefore, its dysregulation stands as a leading substrate for repetitive behaviors. However, beyond indirect evidence, specific assessment of nigral DA neuron activity in ASD and FXS models is lacking. Here, we show that hyperactivity of substantia nigra pars compacta (SNpc) DA neurons is an early feature of FXS. The underlying mechanisms rely on mGluR1 and ErbB receptors. Up-regulation of ErbB4 and ErbB2 in nigral DA neurons drives neuronal hyperactivity and repetitive behaviors of the FXS mouse, simultaneously rescued by ErbB inhibition. In conclusion, beyond providing the first evidence of dysregulation of the SNpc DA nucleus in FXS, we identify novel targets - ErbB receptors - whose inhibition proficiently attenuates repetitive behaviors, thus opening an avenue toward innovative therapies for ASD and FXS.

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

Cited by 4 publications

References 108 publications

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

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

Striatal insights: a cellular and molecular perspective on repetitive behaviors in pathology

ErbB inhibition rescues nigral dopamine neuron hyperactivity and repetitive behaviors in a mouse model of fragile X syndrome

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