L'appauvrissement ciblé de l'interneuron dans le striatum dorsal produit des anomalies comportementales autistiques chez les souris mâles mais pas femelles.

Aperçu: G.M.

La pathologie interneuronaire est impliquée dans de nombreux troubles neuropsychiatriques.
Les interneurons du striatum, y compris les interneurones à forte amplification exprimant la parvalbumine (FSI) et les grands interneurones cholinergiques (CIN), sont affectés chez les patients atteints de TS (Syndrome de la Tourette) et dans des modèles précliniques de TSA et TS.

Pour tester l'importance causale de ces anomalies neuronales, elles ont été récapitulés in vivo chez des souris normales en utilisant une combinaison de stratégie viral transgénique pour l'ablation ciblée par la toxine.

L'épuisement de 50% des FSI et des CIN dans le striatum dorsal de souris mâles produit une stéréotypie spontanée et des déficits marqués dans l'interaction sociale. D'une manière frappante, ces effets de comportement ne sont pas observés chez les souris femelles.

Biol Psychiatry. 2017 Feb 10. pii: S0006-3223(17)30095-1. doi: 10.1016/j.biopsych.2017.01.020.

Targeted Interneuron Depletion in the Dorsal Striatum Produces Autism-like Behavioral Abnormalities in Male but Not Female Mice

Rapanelli M¹, Frick LR¹, Xu M¹, Groman SM¹, Jindachomthong K¹, Tamamaki N², Tanahira C², Taylor JR³, Pittenger C⁴.

Author information

1

Department of Psychiatry, Yale University, New Haven, Connecticut.

2

Department of Morphological Neural Science, Graduate School of Medicine, Kumamoto University, Honjo, Kumamoto, Japan.

3

Department of Psychiatry, Yale University, New Haven, Connecticut; Department of Psychology, Yale University, New Haven, Connecticut.

4

Department of Psychiatry, Yale University, New Haven, Connecticut; Department of Psychology, Yale University, New Haven, Connecticut; Child Study Center, Yale University, New Haven, Connecticut; Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut. Electronic address: christopher.pittenger@yale.edu

Abstract

BACKGROUND:

Interneuronal pathology is implicated in many neuropsychiatric disorders, including autism spectrum disorder (ASD) and Tourette syndrome (TS). Interneurons of the striatum, including the parvalbumin-expressing fast-spiking interneurons (FSIs) and the large cholinergic interneurons (CINs), are affected in patients with TS and in preclinical models of both ASD and TS.

METHODS:

To test the causal importance of these neuronal abnormalities, we recapitulated them in vivo in developmentally normal mice using a combination transgenic-viral strategy for targeted toxin-mediated ablation.

RESULTS:

We found that conjoint ~50% depletion of FSIs and CINs in the dorsal striatum of male mice produces spontaneous stereotypy and marked deficits in social interaction. Strikingly, these behavioral effects are not seen in female mice; because ASD and TS have a marked male predominance, this observation reinforces the potential relevance of the finding to human disease. Neither of these effects is seen when only one or the other interneuronal population is depleted; ablation of both is required. Depletion of FSIs, but not of CINs, also produces anxiety-like behavior, as has been described previously. Behavioral pathology in male mice after conjoint FSI and CIN depletion is accompanied by increases in activity-dependent signaling in the dorsal striatum; these alterations were not observed after disruption of only one interneuron type or in doubly depleted female mice.

CONCLUSIONS:

These data indicate that disruption of CIN and FSI interneurons in the dorsal striatum is sufficient to produce network and behavioral changes of potential relevance to ASD, in a sexually dimorphic manner.

Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

Anxiety; Autism spectrum disorder; Interneuron; Social preference; Stereotypy; Striatum

PMID: 28347488

DOI: 10.1016/j.biopsych.2017.01.020