Rapanelli Maximiliano, Frick Luciana Romina, Xu Meiyu, Groman Stephanie Mary, Jindachomthong Kantiya, Tamamaki Nobuaki, Tanahira Chiyoko, Taylor Jane Rebecca, Pittenger Christopher
Department of Psychiatry, Yale University, New Haven, Connecticut.
Department of Morphological Neural Science, Graduate School of Medicine, Kumamoto University, Honjo, Kumamoto, Japan.
Biol Psychiatry. 2017 Aug 1;82(3):194-203. doi: 10.1016/j.biopsych.2017.01.020. Epub 2017 Feb 10.
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.
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.
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.
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.
神经元间病理改变与许多神经精神疾病有关，包括自闭症谱系障碍（ASD）和抽动秽语综合征（TS）。纹状体中间神经元，包括表达小白蛋白的快速放电中间神经元（FSIs）和大型胆碱能中间神经元（CINs），在TS患者以及ASD和TS的临床前模型中均受到影响。
为了测试这些神经元异常的因果重要性，我们使用转基因病毒靶向毒素介导的消融策略，在发育正常的小鼠体内重现了这些异常。
我们发现，雄性小鼠背侧纹状体中FSIs和CINs联合减少约50%会导致自发刻板行为和社交互动明显缺陷。令人惊讶的是，雌性小鼠未出现这些行为影响；由于ASD和TS在男性中明显更为常见，这一观察结果强化了该发现与人类疾病的潜在相关性。当仅减少其中一种中间神经元群体时，不会出现这些影响；两种都需要消融。如先前所述，FSIs而非CINs的减少也会产生焦虑样行为。联合消融FSIs和CINs后，雄性小鼠的行为病理学伴随着背侧纹状体中活性依赖性信号传导的增加；仅破坏一种中间神经元类型或在双重减少的雌性小鼠中未观察到这些改变。
这些数据表明，背侧纹状体中CIN和FSI中间神经元的破坏足以以性别二态性方式产生与ASD潜在相关的网络和行为变化。
