Neuronal signature of social novelty exploration in the VTA: implication for Autism Spectrum Disorder

AbstractNovel stimuli attract our attention, promote exploratory behavior, and facilitate learning. Atypical habituation and aberrant novelty exploration have been related with the severity of Autism Spectrum Disorders (ASD) but the underlying neuronal circuits are unknown. Here, we report that dopamine (DA) neurons of the ventral tegmental area (VTA) promote the behavioral responses to novel social stimuli, support preference for social novelty, and mediate the reinforcing properties of novel social interaction. Social novelty exploration is associated with the insertion of calcium-permeable GluA2-lacking AMPA-type glutamate receptors at excitatory synapses on VTA DA neurons. These novelty-dependent synaptic adaptations only persist upon repeated exposure to social stimuli and sustain social interaction. Global or DA neuron-specific inactivation of the ASD risk gene Neuroligin3 alters both social novelty exploration and the reinforcing properties of social stimuli. These behavioral deficits are accompanied by an aberrant expression of non-canonical GluA2-lacking AMPA-receptors at excitatory synapses on VTA DA neurons and an occlusion of novelty-induced synaptic plasticity. Altogether, these findings causally link impaired novelty exploration in an ASD mouse model to VTA DA circuit dysfunction.

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Hippocampal neurons isolated from rats subjected to the valproic acid model mimic in vivo synaptic pattern: evidence of neuronal priming during early development in autism spectrum disorders

Molecular Autism ◽

10.1186/s13229-021-00428-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marianela Evelyn Traetta ◽

Martín Gabriel Codagnone ◽

Nonthué Alejandra Uccelli ◽

Alberto Javier Ramos ◽

Sandra Zárate ◽

...

Keyword(s):

Valproic Acid ◽

Autism Spectrum Disorders ◽

Cell Adhesion ◽

Hippocampal Neurons ◽

Primary Cultures ◽

Autism Spectrum ◽

Excitatory Synapses ◽

Behavioral Deficits ◽

Spectrum Disorders

Abstract Background Autism spectrum disorders (ASD) are synaptopathies characterized by area-specific synaptic alterations and neuroinflammation. Structural and adhesive features of hippocampal synapses have been described in the valproic acid (VPA) model. However, neuronal and microglial contribution to hippocampal synaptic pattern and its time-course of appearance is still unknown. Methods Male pups born from pregnant rats injected at embryonic day 10.5 with VPA (450 mg/kg, i.p.) or saline (control) were used. Maturation, exploratory activity and social interaction were assessed as autistic-like traits. Synaptic, cell adhesion and microglial markers were evaluated in the CA3 hippocampal region at postnatal day (PND) 3 and 35. Primary cultures of hippocampal neurons from control and VPA animals were used to study synaptic features and glutamate-induced structural remodeling. Basal and stimuli-mediated reactivity was assessed on microglia primary cultures isolated from control and VPA animals. Results At PND3, before VPA behavioral deficits were evident, synaptophysin immunoreactivity and the balance between the neuronal cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) were preserved in the hippocampus of VPA animals along with the absence of microgliosis. At PND35, concomitantly with the establishment of behavioral deficits, the hippocampus of VPA rats showed fewer excitatory synapses and increased NCAM/PSA-NCAM balance without microgliosis. Hippocampal neurons from VPA animals in culture exhibited a preserved synaptic puncta number at the beginning of the synaptogenic period in vitro but showed fewer excitatory synapses as well as increased NCAM/PSA-NCAM balance and resistance to glutamate-induced structural synaptic remodeling after active synaptogenesis. Microglial cells isolated from VPA animals and cultured in the absence of neurons showed similar basal and stimuli-induced reactivity to the control group. Results indicate that in the absence of glia, hippocampal neurons from VPA animals mirrored the in vivo synaptic pattern and suggest that while neurons are primed during the prenatal period, hippocampal microglia are not intrinsically altered. Conclusions Our study suggests microglial role is not determinant for developing neuronal alterations or counteracting neuronal outcome in the hippocampus and highlights the crucial role of hippocampal neurons and structural plasticity in the establishment of the synaptic alterations in the VPA rat model.

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Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

Molecular Psychiatry ◽

10.1038/s41380-021-01140-y ◽

2021 ◽

Author(s):

Ahmed Eltokhi ◽

Miguel A. Gonzalez-Lozano ◽

Lars-Lennart Oettl ◽

Andrey Rozov ◽

Claudia Pitzer ◽

...

Keyword(s):

Synaptic Plasticity ◽

Social Interaction ◽

Social Behavior ◽

Ampa Receptors ◽

Signal To Noise Ratio ◽

Signal Transmission ◽

Neuropsychiatric Disorders ◽

Autism Spectrum ◽

Strong Impact ◽

Odor Processing

AbstractMutations in SHANK genes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported in Shank KO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK proteins, but these remain poorly defined. In this study, we examined how SHANK2 can mediate electrophysiological, molecular, and behavioral effects by conditionally overexpressing either wild-type SHANK2A or the extrasynaptic SHANK2A(R462X) variant. SHANK2A overexpression affected pre- and postsynaptic targets and revealed a reversible, development-dependent autism spectrum disorder-like behavior. SHANK2A also mediated redistribution of Ca2+-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, leading to impaired synaptic plasticity in the basal dendrites. Moreover, SHANK2A overexpression reduced social interaction and increased the excitatory noise in the olfactory cortex during odor processing. In contrast, overexpression of the extrasynaptic SHANK2A(R462X) variant did not impair hippocampal synaptic plasticity, but still altered the expression of presynaptic/axonal signaling proteins. We also observed an attention-deficit/hyperactivity-like behavior and improved social interaction along with enhanced signal-to-noise ratio in cortical odor processing. Our results suggest that the disruption of pre- and postsynaptic SHANK2 functions caused by SHANK2 mutations has a strong impact on social behavior. These findings indicate that pre- and postsynaptic SHANK2 actions cooperate for normal neuronal function, and that an imbalance between these functions may lead to different neuropsychiatric disorders.

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Parent-mediated early intervention for young children with autism spectrum disorders (ASD)

BJPsych Advances ◽

10.1192/apt.22.3.146 ◽

2016 ◽

Vol 22 (3) ◽

pp. 146-146 ◽

Cited By ~ 1

Author(s):

Inalegwu P. Oono ◽

Emma J. Honey ◽

Helen McConachie

Keyword(s):

Autism Spectrum Disorders ◽

Early Intervention ◽

Social Interaction ◽

Young Children ◽

Cochrane Review ◽

Children With Autism ◽

Autism Spectrum ◽

Young Children With Autism ◽

Spectrum Disorders

Young children with autism spectrum disorders (ASD) have impairments in the areas of communication and social interaction and often display repetitive or non-compliant behaviour. This early pattern of difficulties is a challenge for parents. Therefore, approaches that help parents develop strategies for interaction and management of behaviour are an obvious route for early intervention in ASD. This review updates a Cochrane review first published in 2002 but is based on a new protocol.

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A novel machine learning model to predict autism spectrum disorders risk gene

Neural Computing and Applications ◽

10.1007/s00521-018-3502-5 ◽

2018 ◽

Vol 31 (10) ◽

pp. 6711-6717 ◽

Cited By ~ 3

Author(s):

Murat Gök

Keyword(s):

Machine Learning ◽

Autism Spectrum Disorders ◽

Learning Model ◽

Autism Spectrum ◽

Risk Gene ◽

Machine Learning Model ◽

Spectrum Disorders

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What a Tangible Digital Installation for Museums Can Offer to Autistic Children and Their Teachers

International Journal of Game-Based Learning ◽

10.4018/ijgbl.2016040103 ◽

2016 ◽

Vol 6 (2) ◽

pp. 29-45 ◽

Cited By ~ 1

Author(s):

Emanuela Marchetti ◽

Andrea Valente

Keyword(s):

Autism Spectrum Disorders ◽

Social Interaction ◽

Role Play ◽

Autism Spectrum ◽

Game Based Learning ◽

Conceptual Thinking ◽

History Learning ◽

Positive Experiences ◽

Spectrum Disorders ◽

Danish School

This study is a cooperation between the authors and a teacher who works with pupils affected by autism spectrum disorders (9-12 years old) in a primary Danish school. The aim was assess the benefits of game-based learning with respect to teachers' main challenges: facilitating the discussion of curricular subjects and enabling learning through conceptual thinking and social interaction. An existing digital and tangible installation called MicroCulture, originally created by the authors to bridge history learning across museums and schools was re-contextualised and placed at the school's disposal, in a three weeks study involving 15 pupils. Data was gathered unobtrusively, with qualitative methods. Through mediated play and teacher's facilitation, children occasionally engaged in interactions leading to conceptual thinking, cooperation, and forms of role play. The authors present both problems and positive experiences the pupils and teachers had in playing at MicroCulture; the findings allowed us to outline guidelines for developing similar installations.

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