SHANK3 Downregulation in the Ventral Tegmental Area Accelerates the Extinction of Contextual Associations Induced by Juvenile Non-familiar Conspecific Interaction

Bariselli, Sebastiano; Contestabile, Alessandro; Tzanoulinou, Stamatina; Musardo, Stefano; Bellone, Camilla

doi:10.3389/fnmol.2018.00360

Cited by 18 publications

(25 citation statements)

References 69 publications

(88 reference statements)

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“…However, one brain region that is strongly associated with Shank3-dependent social and repetitive behavioral deficits is the striatum (Peca et al, 2011; Filice et al, 2016; Fuccillo, 2016; Jaramillo et al, 2016, 2017; Mei et al, 2016; Peixoto et al, 2016; Wang et al, 2016, 2017; Zhou et al, 2016; Lee Y. et al, 2017; Reim et al, 2017; Vicidomini et al, 2017; Bey et al, 2018; Fourie et al, 2018; Yoo et al, 2018). More recently, the ventral striatum and its upstream regions (ventral tegmental area and dorsal raphe nucleus) have been implicated in the social deficits in Shank3 -mutant mice (Bariselli et al, 2016, 2018; Bariselli and Bellone, 2017; Luo et al, 2017). Intriguingly, however, our electrophysiological results indicated that Emx1-Cre;Shank3 Δ14–16 mice do not display altered excitatory or inhibitory synaptic transmission in dorsolateral striatal neurons (Figure 4), a finding that strongly contrasts with the reduced excitatory synaptic transmission in dorsolateral striatal neurons in global Shank3 Δ14–16 and Viaat-Cre;Shank3 Δ14–16 mice (Yoo et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Shank3 Exons 14–16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability

Yoo

Cho

Park

et al. 2019

Front. Cell. Neurosci.

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Shank3, an abundant excitatory postsynaptic scaffolding protein, has been associated with multiple brain disorders, including autism spectrum disorders (ASD) and Phelan-McDermid syndrome (PMS). However, how cell type-specific Shank3 deletion affects disease-related neuronal and brain functions remains largely unclear. Here, we investigated the impacts of Shank3 deletion in glutamatergic neurons on synaptic and behavioral phenotypes in mice and compared results with those previously obtained from mice with global Shank3 mutation and GABAergic neuron-specific Shank3 mutation. Neuronal excitability was abnormally increased in layer 2/3 pyramidal neurons in the medial prefrontal cortex (mPFC) in mice with a glutamatergic Shank3 deletion, similar to results obtained in mice with a global Shank3 deletion. In addition, excitatory synaptic transmission was abnormally increased in layer 2/3 neurons in mice with a global, but not a glutamatergic, Shank3 deletion, suggesting that Shank3 in glutamatergic neurons are important for the increased neuronal excitability, but not for the increased excitatory synaptic transmission. Neither excitatory nor inhibitory synaptic transmission was altered in the dorsal striatum of Shank3-deficient glutamatergic neurons, a finding that contrasts with the decreased excitatory synaptic transmission in global and Shank3-deficient GABAergic neurons. Behaviorally, glutamatergic Shank3-deficient mice displayed abnormally increased direct social interaction and repetitive self-grooming, similar to global and GABAergic Shank3-deficient mice. These results suggest that glutamatergic and GABAergic Shank3 deletions lead to distinct synaptic and neuronal changes in cortical layer 2/3 and dorsal striatal neurons, but cause similar social and repetitive behavioral abnormalities likely through distinct mechanisms.

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Section: Discussionmentioning

confidence: 99%

Shank3 Exons 14–16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability

Yoo

Cho

Park

et al. 2019

Front. Cell. Neurosci.

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“…A number of studies reported defective habituation in idiopathic ASD (Dinstein et al, 2012; Ewbank et al, 2015; Kleinhans et al, 2009; Pellicano et al, 2013). Habituation deficits have also been demonstrated in patients with FXS and in its mouse model (Restivo et al, 2005), as well as in a number of other ID/ASD mouse, zebrafish and fly models (Bariselli et al, 2018; Stessman et al, 2017; Wolman et al, 2014). Different types of habituation have been described in Drosophila , and a variety of assays are available for their assessment (Asztalos et al, 2007; Das et al, 2011; Kuntz et al, 2012; Paranjpe et al, 2012).…”

Section: Using Drosophila To Overcome Bottlenecks In Id and Asd Reseamentioning

confidence: 96%

Intellectual disability and autism spectrum disorders ‘on the fly’: insights from Drosophila

Coll-Tané

Krebbers

Zweier

et al. 2019

Disease Models &Amp; Mechanisms

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Intellectual disability (ID) and autism spectrum disorders (ASD) are frequently co-occurring neurodevelopmental disorders and affect 2-3% of the population. Rapid advances in exome and genome sequencing have increased the number of known implicated genes by threefold, to more than a thousand. The main challenges in the field are now to understand the various pathomechanisms associated with this bewildering number of genetic disorders, to identify new genes and to establish causality of variants in still-undiagnosed cases, and to work towards causal treatment options that so far are available only for a few metabolic conditions. To meet these challenges, the research community needs highly efficient model systems. With an increasing number of relevant assays and rapidly developing novel methodologies, the fruit fly Drosophila melanogaster is ideally positioned to change gear in ID and ASD research. The aim of this Review is to summarize some of the exciting work that already has drawn attention to Drosophila as a model for these disorders. We highlight well-established ID- and ASD-relevant fly phenotypes at the (sub)cellular, brain and behavioral levels, and discuss strategies of how this extraordinarily efficient and versatile model can contribute to ‘next generation’ medical genomics and to a better understanding of these disorders.

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“…It is also worth mentioning that a common aspect of these studies is that they used a rat of the same weight and gender as the social stimulus, whereas in our study a younger conspecific was employed (one month old vs three months old). The reason for including a juvenile mouse is that it was found to be more reinforcing than an age-matched non-familiar animal in the CPP paradigm (Bariselli et al, 2018). Another interesting point is that we used a mouse strain (C57BL/6J) which is known to be prone to cocaine self-administration (Thomsen and Caine, 2011), as well as cocaine-induced CPP (Wang et al, 2014) and, despite this fact, we found a beneficial effect of social factor.…”

Section: Discussionmentioning

confidence: 99%

The presence of a social stimulus reduces cocaine-seeking in a place preference conditioning paradigm

et al. 2019

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Background: One challenge in the treatment of substance use disorders is to re-engage the interest toward non-drug-related activities. Among these activities, social interaction has had a prominent role due to its positive influence on treatment outcome. Aims and methods: Our aim was to study whether the presence of a social stimulus during the cocaine-induced conditioned place preference test was able to reduce the time spent in the drug-paired compartment. For that purpose, mice were trained for four days on a conditioned place preference task with one compartment paired with cocaine and the opposite with saline. On the test day, we introduced an unfamiliar juvenile male mouse into the saline-conditioned compartment (inside a pencil cup) to analyse the animal preference towards the two rewarding stimuli (cocaine vs mouse). Additionally, to discard the possible effect of novelty, as well as the housing condition (social isolation) on social preference, we decided to include a novel object during the test session, as well as perform the same conditioned place preference protocol with a group of animals in social housing conditions. Results: The social stimulus was able to reduce the preference for cocaine and enhance the active interaction with the juvenile mouse (sniffing) compared to the empty pencil cup paired with the drug. The introduction of a novel object during the test session did not reduce the preference for the cocaine-paired compartment, and interestingly, the preference for the social stimulus was independent of the housing condition. c-Fos immunohistochemistry revealed a different pattern of activation based on cocaine-paired conditioning or the presence of social stimulus. Conclusions: These results suggest that social interaction could constitute a valuable component in the treatment of substance use disorders by reducing the salience of the drug.

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SHANK3 Downregulation in the Ventral Tegmental Area Accelerates the Extinction of Contextual Associations Induced by Juvenile Non-familiar Conspecific Interaction

Cited by 18 publications

References 69 publications

Shank3 Exons 14–16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability

Shank3 Exons 14–16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability

Intellectual disability and autism spectrum disorders ‘on the fly’: insights from Drosophila

The presence of a social stimulus reduces cocaine-seeking in a place preference conditioning paradigm

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