Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism

Wang, Wenting; Li, Chenchen; Chen, Qian; Goes, Marie-Sophie van der; Hawrot, James; Yao, Annie Y.; Xian, Gao; Lu, Congyi; Zang, Ying; Zhang, Qiangge; Lyman, Katherine L.; Wang, Dongqing; Guo, Baolin; Wu, Sheng Xi; Gerfen, Charles R.; Fu, Zhanyan; Feng, Guoping

doi:10.1172/jci87997

Cited by 137 publications

(165 citation statements)

References 106 publications

(121 reference statements)

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“… and a later report (Wang et al . ) reported significant overgrooming and striking skin lesions in the Shank3/F KO mice. Consistent with this, SmartCube also picked up increased grooming in Shank3/F KO mice as a top behavioral feature.…”

Section: Discussionmentioning

confidence: 97%

Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder

Kabitzke

Brunner

et al. 2017

Genes Brain and Behavior

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To expand, analyze and extend published behavioral phenotypes relevant to autism spectrum disorder (ASD), we present a study of three ASD genetic mouse models: Feng's Shank3 model, hereafter Shank3/F, Jiang's Shank3 model, hereafter Shank3/J and the Cacna1c deletion model. The Shank3 models mimick gene mutations associated with Phelan-McDermid Syndrome and the Cacna1c model recapitulates the deletion underlying Timothy syndrome. This study utilizes both standard and novel behavioral tests with the same methodology used in our previously published companion report on the Cntnap2 null and 16p11.2 deletion models. We found that some but not all behaviors replicated published findings and those that did replicate, such as social behavior and overgrooming in Shank3 models, tended to be milder than reported elsewhere. The Shank3/F model, and to a much lesser extent, the Shank3/J and Cacna1c models, showed hypoactivity and a general anxiety-like behavior triggered by external stimuli which pervaded social interactions. We did not detect deficits in a cognitive procedural learning test nor did we observe perseverative behavior in these models. We did, however, find differences in exploratory patterns of Cacna1c mutant mice suggestive of a behavioral effect in a social setting. In addition, only Shank3/F showed differences in sensory-gating. Both positive and negative results from this study will be useful in identifying the most robust and replicable behavioral signatures within and across mouse models of autism. Understanding these phenotypes may shed light of which features to study when screening compounds for potential therapeutic interventions.

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Section: Discussionmentioning

confidence: 97%

Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder

Kabitzke

Brunner

et al. 2017

Genes Brain and Behavior

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“…This topic has remained controversial despite several reports of LTD occurring in both MSN subtypes (Bagetta et al, 2011; Picconi et al, 2011; Shen et al, 2008; Wang et al, 2006, 2017; Wu et al, 2015). We showed that LTD can be induced in both dMSNs and iMSNs using HFS, which is consistent with previous findings (Wang et al, 2006, 2017). …”

Section: Discussionmentioning

confidence: 99%

“…A few reports have suggested that this is the case (Kreitzer and Mal-enka, 2005; Shen et al, 2008; Trusel et al, 2015). However, eCB-LTD at synapses onto dMSNs has been observed (Bagetta et al, 2011; Picconi et al, 2011; Shen et al, 2008; Wang et al, 2006, 2017; Wu et al, 2015) and is prevented by the D2R antagonist in these neurons (Bagetta et al, 2011; Wang et al, 2006). It seems unlikely that iMSN D2Rs can account for all of the roles of the receptor in LTD induction.…”

Section: Introductionmentioning

confidence: 99%

Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

2018

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SUMMARY Endocannabinoid (eCB)-mediated long-term depres-sion (LTD) requires dopamine (DA) D2 receptors (D2Rs) for eCB mobilization. The cellular locus of the D2Rs involved in LTD induction remains highly debated. We directly examined the role in LTD induc-tion of D2Rs expressed by striatal cholinergic inter-neurons (Chls) and indirect pathway medium spiny neurons (iMSNs) using neuron-specific targeted deletion of D2Rs. Deletion of Chl-D2Rs (Chl-Drd2KO) impaired LTD induction in both subtypes of MSNs. LTD induction was restored in the Chl-Drd2KO mice by an M1-selective muscarinic acetylcholine receptor antagonist. In contrast, after the deletion of iMSN-D2Rs (iMSN-Drd2KO), LTD induction was intact in MSNs. Separate interrogation of direct pathway and iMSNs revealed a deficit in LTD induction only at syn-apses onto iMSNs that lack D2Rs. LTD induction in iMSNs was restored by D2R agonist application. Our findings suggest that Chl D2Rs strongly modulate LTD induction in MSNs, with iMSN-D2Rs having a weaker, iMSN-specific, modulatory effect.

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“…Evidence for reduced excitatory neurotransmission, long‐term potentiation, NMDA/AMPA ratio, and dendritic spine abnormalities in Shank3B mice formed the basis of our hypothesis that pharmacologically increasing glutamatergic neurotransmission could improve social behaviors and/or reduce repetitive behaviors in Shank3B . To investigate the possibility that enhancing glutamatergic synaptic transmission and increasing glutamatergic excitation could reverse autism‐relevant phenotypes in Shank3B mice [Lovinger, ; Wang et al, ], three classes of pharmacological compounds were evaluated in Shank3B and their wildtype littermate controls: (a) a partial agonist at the glycine modulatory site on the NMDA receptor, d‐cycloserine, that has been evaluated preclinically and in clinical trials for several neuropsychiatric disorders [Baxter et al, ; Myers & Carlezon, ; Schade & Paulus, ]; (b) an Ampakine positive allosteric modulator of the glutamatergic AMPA receptor, CX546, one of a class of compounds found to improve cognition in rodents and tested in clinical trials for schizophrenia and Fragile X syndrome [Goff et al, ; Berry‐Kravis et al, ; Arai & Kessler, ; Lynch, Palmer, & Gall, ]; and (c) the TrkB agonist 7,8‐DHF, as described above. Two behavioral assays in which Shank3B mice were previously reported to display robust and replicated deficits were employed as outcome measures, male–female reciprocal social interactions and repetitive self‐grooming, along with open field exploratory locomotion as a control for the potential confounds of sedation and hyperactivity after drug treatments.…”

Section: Resultsmentioning

confidence: 99%

“…Dependent on the specific mutation, and the brain region containing the mutation in cases of conditional knockouts, Shank3 mutant mice displayed reduced frequency and amplitude of miniature excitatory postsynaptic currents [Bozdagi et al, ; Peca et al, ], reduced glutamatergic transmission and impaired long‐term potentiation in the hippocampus [Wang et al, ; Yang et al, ; Jaramillo et al, ], reductions in the NMDA/AMPA ratio in hippocampal CA1, prefrontal cortex, and striatal medium spiny neurons [Kouser et al, ; Duffney et al, ; Jaramillo et al, ;. Lee et al, ; Wang et al, ], and resistance to pentyletetrazole‐induced seizures [Dhamne et al, ], indicative of reduced excitatory physiology. Shank3B null mutant mice phenocopy the two diagnostic symptom categories of autism, displaying low scores on social assays and high levels of repetitive self‐grooming [Peca et al, ; Chang et al, ; Wang et al, ; Dhamne et al, ].…”

Section: Introductionmentioning

confidence: 99%

Hypothesis‐driven investigations of diverse pharmacological targets in two mouse models of autism

et al. 2019

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Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA‐approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well‐replicated autism‐relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model. Shank3B is a genetic model of a mutation found in autism and Phelan‐McDermid syndrome, in which deficits in excitatory neurotransmission and synaptic plasticity have been reported. BTBR is an inbred strain model of forms of idiopathic autism in which reduced inhibitory neurotransmission and excessive mTOR signaling have been reported. The GABA‐A receptor agonist gaboxadol significantly reduced repetitive self‐grooming in three independent cohorts of BTBR. The TrkB receptor agonist 7,8‐DHF improved spatial learning in Shank3B mice, and reversed aspects of social deficits in BTBR. CX546, a positive allosteric modulator of the glutamatergic AMPA receptor, and d‐cycloserine, a partial agonist of the glycine site on the glutamatergic NMDA receptor, did not rescue aberrant behaviors in Shank3B mice. The mTOR inhibitor rapamycin did not ameliorate social deficits or repetitive behavior in BTBR mice. Comparison of positive and negative pharmacological outcomes, on multiple phenotypes, evaluated for replicability across independent cohorts, enhances the translational value of mouse models of autism for therapeutic discovery. GABA agonists present opportunities for personalized interventions to treat components of autism spectrum disorder. Autism Res 2019, 12: 401–421 © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. Lay Summary Many of the risk genes for autism impair synapses, the connections between nerve cells in the brain. A drug that reverses the synaptic effects of a mutation could offer a precision therapy. Combining pharmacological and behavioral therapies could reduce symptoms and improve the quality of life for people with autism. Here we report reductions in repetitive behavior by a GABA‐A receptor agonist, gaboxadol, and improvements in social and cognitive behaviors by a TrkB receptor agonist, in mouse models of autism.

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Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism

Cited by 137 publications

References 106 publications

Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder

Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder

Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

Hypothesis‐driven investigations of diverse pharmacological targets in two mouse models of autism

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