The Role of Interneurons in Autism and Tourette Syndrome

Rapanelli, Maximiliano; Frick, Luciana Romina; Pittenger, Christopher

doi:10.1016/j.tins.2017.05.004

Cited by 74 publications

(63 citation statements)

References 88 publications

(98 reference statements)

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“…Re-expression of Nlgn3 in parvalbumin-expressing interneurons is therefore likely to be sufficient to restore inhibitory postsynaptic currents and E/I balance in neuronal circuits, rescuing some aspect of the Nlgn3 y/– mouse phenotype. Theories on the pathophysiology of ASD have hypothesized that some of the symptoms associated with ASD may be caused by an E/I imbalance in the cortex or the striatum ( Rapanelli et al, 2017 ). In Nlgn3 y/– Pvalb Cre/+ mice, restoration of the E/I balance is more likely to occur in the striatum, where we detected re-expression of Nlgn3 , rather than in the cortex, where we detected low levels of re-expression, close to background.…”

Section: Discussionmentioning

confidence: 99%

Male and Female Mice Lacking Neuroligin-3 Modify the Behavior of Their Wild-Type Littermates

Kalbassi

Bachmann

Cross

et al. 2017

eNeuro

119

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In most mammals, including humans, the postnatal acquisition of normal social and nonsocial behavior critically depends on interactions with peers. Here we explore the possibility that mixed-group housing of mice carrying a deletion of Nlgn3, a gene associated with autism spectrum disorders, and their wild-type littermates induces changes in each other’s behavior. We have found that, when raised together, male Nlgn3 knockout mice and their wild-type littermates displayed deficits in sociability. Moreover, social submission in adult male Nlgn3 knockout mice correlated with an increase in their anxiety. Re-expression of Nlgn3 in parvalbumin-expressing cells in transgenic animals rescued their social behavior and alleviated the phenotype of their wild-type littermates, further indicating that the social behavior of Nlgn3 knockout mice has a direct and measurable impact on wild-type animals’ behavior. Finally, we showed that, unlike male mice, female mice lacking Nlgn3 were insensitive to their peers’ behavior but modified the social behavior of their littermates. Altogether, our findings show that the environment is a critical factor in the development of behavioral phenotypes in transgenic and wild-type mice. In addition, these results reveal that the social environment has a sexually dimorphic effect on the behavior of mice lacking Nlgn3, being more influential in males than females.

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Section: Discussionmentioning

confidence: 99%

Male and Female Mice Lacking Neuroligin-3 Modify the Behavior of Their Wild-Type Littermates

Kalbassi

Bachmann

Cross

et al. 2017

eNeuro

119

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“…Animal models with these genetic deficits also show reduced inhibitory tone, recapitulating human patient studies 29 . Some of these neurological disorders are thought to have neurodevelopmental origins, such as ASD and schizophrenia, raising the intriguing questions: Is there a causal link between defective excitatory synaptic function during development and reduced inhibition?…”

Section: Discussionmentioning

confidence: 62%

Cell-autonomous regulation of structural and functional plasticity in inhibitory neurons by excitatory synaptic inputs

Shen

Zheng

et al. 2017

Preprint

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Functional circuit assembly is thought to require coordinated development of excitation and inhibition, but whether they are co-regulated cell-autonomously remains unclear. We investigated effects of decreased glutamatergic synaptic input on inhibitory synapses by expressing AMPAR subunit, GluA1 and GluA2, C-terminal peptides (GluA1CTP and GluA2CTP) in developing Xenopus tectal neurons. GluACTP decreased excitatory synaptic inputs and cell-autonomously decreased inhibitory synaptic inputs in excitatory and inhibitory neurons. Visually-evoked excitatory and inhibitory currents decreased proportionately, maintaining excitation/inhibition. GluACTP affected dendrite structure and visual experience-dependent structural plasticity differently in excitatory and inhibitory neurons. Deficits in excitatory and inhibitory synaptic transmission and experience-dependent plasticity manifested in altered visual receptive field properties. Both visual avoidance behavior and learning-induced behavioral plasticity were impaired, suggesting that maintaining excitation/inhibition alone is insufficient to preserve circuit function. We demonstrate that excitatory synaptic dysfunction in individual neurons cell-autonomously decreases inhibitory inputs and disrupts neuronal and circuit plasticity, information processing and learning.

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“…Although, there are likely other impediments to overcome before hSC-interneurons are fully synchronized with the developmental timescale of host mouse cortex, our findings represent an important step towards harnessing the full potential of hSC-interneurons. Cortical interneurons are critical modulators of brain function (Kepecs and Fishell, 2014;Tremblay et al, 2016) and it is important to develop human interneuron models of disease (Catterall, 2018;Inan et al, 2013;Marin, 2012;Rapanelli et al, 2017). Moreover, our pre-treated hSC-interneurons also exhibit more maturity in vitro, suggesting SPARC/SerpinE1 treatment may also be effective when applied to organoid and monolayer approaches.…”

Section: Discussionmentioning

confidence: 89%

Vascular-Derived SPARC and SerpinE1 Regulate Interneuron Tangential Migration and Accelerate Functional Maturation of Human Stem Cell-Derived Interneurons

Genestine

Ambriz

Crabtree³

et al. 2020

Preprint

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Cortical interneurons establish inhibitory microcircuits throughout the neocortex and their dysfunction has been implicated in epilepsy and neuropsychiatric diseases. Developmentally, interneurons migrate from a distal progenitor domain in order to populate the neocortex -a process that occurs at a slower rate in humans than in mice. In this study, we sought to identify factors that regulate the rate of interneuron maturation across the two species. Using embryonic mouse development as a model system, we found that the process of initiating interneuron migration is regulated by blood vessels of the medial ganglionic eminence (MGE), an interneuron progenitor domain. We identified two endothelial cell-derived paracrine factors, SPARC and SerpinE1, that enhance interneuron migration in mouse MGE explants and organotypic cultures.Moreover, pre-treatment of human stem cell-derived interneurons (hSC-interneurons) with SPARC and SerpinE1 prior to transplantation into neonatal mouse cortex enhanced their migration and morphological elaboration in the host cortex. Further, SPARC and SerpinE1-treated hSC-interneurons also exhibited more mature electrophysiological characteristics compared to controls. Overall, our studies suggest a critical role for CNS vasculature in regulating interneuron developmental maturation in both mice and humans.

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The Role of Interneurons in Autism and Tourette Syndrome

Cited by 74 publications

References 88 publications

Male and Female Mice Lacking Neuroligin-3 Modify the Behavior of Their Wild-Type Littermates

Male and Female Mice Lacking Neuroligin-3 Modify the Behavior of Their Wild-Type Littermates

Cell-autonomous regulation of structural and functional plasticity in inhibitory neurons by excitatory synaptic inputs

Vascular-Derived SPARC and SerpinE1 Regulate Interneuron Tangential Migration and Accelerate Functional Maturation of Human Stem Cell-Derived Interneurons

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