Shank3 Deficiency is Associated With Altered Profile of Neurotransmission Markers in Pups and Adult Mice

Bukatova, Stanislava; Renczés, Emese; Reichova, Alexandra; Filo, Johan; Sadlonova, Anna; Mravec, Boris; Ostatníková, Daniela; Bakoš, Ján; Bačová, Zuzana

doi:10.1007/s11064-021-03435-6

Cited by 16 publications

(11 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accordingly, this re-expression can only save a portion of the behavioral manifestations of autism (Grabrucker et al, 2011a;Peça et al, 2011a;Tai et al, 2020). A similar study showed that early postpartum intervention could improve irreversible behavioral defects in adulthood (Jin et al, 2018;Bukatova et al, 2021). Therefore, this phenomenon emphasizes the unique performance of SHANK3 expression at specific developmental stages and throughout life.…”

Section: Treatment Of Asd and Paresthesia By Targeting Shank3mentioning

confidence: 99%

Targeting Shank3 deficiency and paresthesia in autism spectrum disorder: A brief review

Huang

2023

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders characterized by impaired social communication, social interaction, and repetitive behaviors. Several studies have shown an association between cases of ASD and mutations in the genes of SH3 and multiple ankyrin repeat domain protein 3 (SHANK3). These genes encode many cell adhesion molecules, scaffold proteins, and proteins involved in synaptic transcription, protein synthesis, and degradation. They have a profound impact on all aspects of synaptic transmission and plasticity, including synapse formation and degeneration, suggesting that the pathogenesis of ASD may be partially attributable to synaptic dysfunction. In this review, we summarize the mechanism of synapses related to Shank3 in ASD. We also discuss the molecular, cellular, and functional studies of experimental models of ASD and current autism treatment methods targeting related proteins.

show abstract

Section: Treatment Of Asd and Paresthesia By Targeting Shank3mentioning

confidence: 99%

Targeting Shank3 deficiency and paresthesia in autism spectrum disorder: A brief review

Huang

2023

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Increasing activity in this region using DREADDs re-established social bonding in ASD mice, providing strong anatomical and physiological information on the biological origin of the development of this ASD deficit. Altered neurotransmitter systems are evident early during postnatal development in the hypothalamus, with neonatal mice lacking Shank3 showing decreases in GABAergic and glutamatergic markers, but increases in cholinergic, dopaminergic, and serotonergic markers that may underpin adult ASD phenotypes ( Bukatova et al, 2021 ).…”

Section: Other Brain Regionsmentioning

confidence: 99%

Shankopathies in the Developing Brain in Autism Spectrum Disorders

et al. 2021

View full text Add to dashboard Cite

The SHANK family of proteins play critical structural and functional roles in the postsynaptic density (PSD) at excitatory glutamatergic synapses. Through their multidomain structure they form a structural platform across the PSD for protein–protein interactions, as well as recruiting protein complexes to strengthen excitatory synaptic transmission. Mutations in SHANKs reflect their importance to synapse development and plasticity. This is evident in autism spectrum disorder (ASD), a neurodevelopmental disorder resulting in behavioural changes including repetitive behaviours, lack of sociability, sensory issues, learning, and language impairments. Human genetic studies have revealed ASD mutations commonly occur in SHANKs. Rodent models expressing these mutations display ASD behavioural impairments, and a subset of these deficits are rescued by reintroduction of Shank in adult animals, suggesting that lack of SHANK during key developmental periods can lead to permanent changes in the brain’s wiring. Here we explore the differences in synaptic function and plasticity from development onward in rodent Shank ASD models. To date the most explored brain regions, relate to the behavioural changes observed, e.g., the striatum, hippocampus, sensory, and prefrontal cortex. In addition, less-studied regions including the hypothalamus, cerebellum, and peripheral nervous system are also affected. Synaptic phenotypes include weakened but also strengthened synaptic function, with NMDA receptors commonly affected, as well as changes in the balance of excitation and inhibition especially in cortical brain circuits. The effects of shankopathies in activity-dependent brain wiring is an important target for therapeutic intervention. We therefore highlight areas of research consensus and identify remaining questions and challenges.

show abstract

“…Consistent with its important role in social behavior, imaging studies of ASD patients show abnormal activity in NAc 31,32 , as well as changes in functional connectivity within frontostriatal [33][34][35] and striatal 36 circuits. Accordingly, ASD mouse models display altered NAc synaptic plasticity and transmission [37][38][39] , as well as changes in gene expression of inhibitory and excitatory markers 40 in adult animals. Importantly, manipulations targeted to the NAc can mimic 41 or rescue behavior deficits in a range of ASD mouse models 37,[42][43][44] , further implicating the NAc in ASD pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

Maturation of Nucleus Accumbens Synaptic Transmission Signals a Critical Period for the Rescue of Social Deficits in a Mouse Model of Autism Spectrum Disorder

Matthiesen

Khlaifia

Steininger

et al. 2023

Preprint

View full text Add to dashboard Cite

Social behavior emerges early in development, a time marked by the onset of neurodevelopmental disorders featuring social deficits, including autism spectrum disorder (ASD). Although deficits in social interaction and communication are at the core of the clinical diagnosis of ASD, very little is known about their neural correlates at the time of clinical onset of the disorder. The nucleus accumbens (NAc), a brain region extensively implicated in social behavior, undergoes synaptic, cellular and molecular alterations in early life, and is particularly affected in ASD mouse models. To explore a link between the maturation of the NAc and neurodevelopmental deficits in social behavior, we compared age-dependent changes in spontaneous synaptic transmission in NAc shell medium spiny neurons (MSNs) between the highly social C57BL/6J mouse strain and the idiopathic ASD mouse model BTBR T+ Itpr3tf/J at postnatal day (P) 4, P6, P8, P12, P15, P21 and P30. We found that MSNs from both C57BL/6J and BTBR mice display age-dependent increases in spontaneous excitatory and inhibitory synaptic currents between P4 and P30. Comparison of NAc spontaneous transmission between strains showed that BTBR MSNs display increased excitatory transmission during the first postnatal week, and increased inhibition across the first, second and fourth postnatal weeks, suggesting accelerated maturation of excitatory and inhibitory synaptic inputs onto BTBR MSNs compared to C57BL/6J mice. These early life changes in synaptic transmission are consistent with a potential critical period in the maturation of the NAc, which could maximize the efficacy of interventions affecting social behavior. To test this possibility, we treated BTBR mice in either early life (P4-P8) or adulthood (P60-P64) with the mTORC1 antagonist rapamycin, a well-established rescue intervention for ASD-like behavior. We found that rapamycin treatment rescued social interaction deficits in BTBR mice when injected in infancy, but not in adulthood. These data emphasize the importance of studying brain regions involved in the pathophysiology of neurodevelopmental disorders at clinically-relevant time points, which may offer novel insight into the timing and targets of therapeutic interventions to maximize positive outcomes.

show abstract

Shank3 Deficiency is Associated With Altered Profile of Neurotransmission Markers in Pups and Adult Mice

Cited by 16 publications

References 54 publications

Targeting Shank3 deficiency and paresthesia in autism spectrum disorder: A brief review

Targeting Shank3 deficiency and paresthesia in autism spectrum disorder: A brief review

Shankopathies in the Developing Brain in Autism Spectrum Disorders

Maturation of Nucleus Accumbens Synaptic Transmission Signals a Critical Period for the Rescue of Social Deficits in a Mouse Model of Autism Spectrum Disorder

Contact Info

Product

Resources

About