Towards understanding cellular mechanisms of positive symptoms of schizophrenia

精神分裂症(SCZ)影响着世界约1%的人口，其特征是症状 包括幻觉和妄想(阳性症状)；反社会行为和迟钝的情绪 (阴性症状)；工作记忆、执行功能、学习和记忆缺陷(认知 症状)。主要通过多巴胺受体(Drd2)发挥作用的抗精神病药物可以缓解阳性症状， 一些阴性症状，大多对认知症状无效。因此，多个神经回路和 机制与SCZ症状类别有关。因为SCZ的病因是未知的和有效的 小鼠模型不可用，我们重点关注最常见的22q11.2缺失综合征(22q11DS) 人类的微缺失综合征，这会使患SCZ的风险增加30倍。精神病症状在临床上是 在伴有或不伴有22q11DS的SCZ患者中无法区分，通常出现在青春期晚期/早期 成人期。建立了22q11DS小鼠模型(22q11DS小鼠)，并进行了验证。利用这些老鼠， 我们和其他人已经确定了一些认知和负面情绪背后的细胞和分子机制 22q11DS的症状。在之前的资助期间，我们还发现了突触传递中断 在22q11DS小鼠的听觉丘脑和听觉皮质(ACX)之间的丘脑皮质(TC)投射中。 人类这些脑区的异常活动与幻听有关。TC中断 老鼠的投影出现在3.5个月大的时候，这对应于人类的青春期晚期/成年期早期， 出现阳性症状的年龄，并通过抗精神病药物和DRD2s的特定抑制剂拯救。我们的研究 揭示TC缺陷是由于丘脑传入的谷氨酸释放减少所致，这是由于 介导microRNA(MiR)生物合成的22q11DS基因Dgcr8单倍体不足。Dgcr8 单倍体不足导致miR-338-3p耗尽，进而提高丘脑中继神经元中Drd2的水平。 升高的Drd2s减少了丘脑神经元中谷氨酸的释放。MiR-338-3p的表达在 丘脑随着年龄的增长而衰退，这可能是丘脑的特异性和迟发性发病机制的基础。 TC中断的可能性。尽管TC机制似乎满足了调解阳性症状的要求， 它如何影响ACX和听觉丘脑的网络活动尚不清楚。在这项竞争性续订申请中， 我们建议分析ACX和听觉丘脑神经元团的异常自发活动。 在老鼠的行为上。对于ACX，我们将通过颅窗使用双光子成像，对于听觉 丘脑，我们将使用头部附着式迷你望远镜(单光子成像)或通过分级指数进行双光子成像 隐形眼镜。我们还将研究miR-338-3p表达随年龄增长而下降的机制。 并将其与22q11DS模型ACX的同步性异常起病晚有关。这项工作将阐明 SCZ最神秘症状的新机制，为SCZ的发展提供了框架 具体的治疗干预措施，以减轻这种灾难性疾病患者的阳性症状。

Schizophrenia (SCZ) affects about 1% of the world’s population and is characterized by symptoms that include hallucinations and delusions (positive symptoms); antisocial behavior and blunted emotions (negative symptoms); and deficits in working memory, executive function, and learning and memory (cognitive symptoms). Antipsychotics primarily acting through dopamine receptors (Drd2s) alleviate positive symptoms, some negative symptoms, and are mostly ineffective for cognitive symptoms. Thus, multiple neural circuits and mechanisms are implicated in SCZ symptom categories. Because the etiology of SCZ is unknown and valid SCZ mouse models are not available, we focus on 22q11.2 deletion syndrome (22q11DS), the most common microdeletion syndrome in humans, which increases the risk of SCZ 30 fold. Psychotic symptoms are clinically indistinguishable in patients with SCZ with or without 22q11DS and usually appear during late adolescence/early adulthood. Mouse models of 22q11DS (22q11DS mice) have been constructed and validated. Using these mice, we and others have identified cellular and molecular mechanisms underlying some cognitive and negative symptoms of 22q11DS. During the previous funding period, we also identified disrupted synaptic transmission in thalamocortical (TC) projections between the auditory thalamus and auditory cortex (ACx) in 22q11DS mice. Abnormal activity in these brain regions in humans is associated with auditory hallucinations. Disruption of TC projections occurs in mice at 3.5 months, which corresponds to late adolescence/early adulthood in humans, the age of positive symptom onset, and is rescued by antipsychotics and specific inhibitors of Drd2s. Our studies revealed that the TC deficit is caused by reduced glutamate release from thalamic afferents, resulting from the haploinsufficiency of the 22q11DS gene Dgcr8, which mediates microRNA (miR) biosynthesis. Dgcr8 haploinsufficiency leads to depletion of miR-338-3p, which in turn, elevates Drd2 levels in thalamic relay neurons. Elevated Drd2s decrease glutamate release in thalamic neurons. The expression of miR-338-3p is enriched in the thalamus and declines with age, which may underlie thalamus specificity and the mechanism of late onset of TC disruption. Although the TC mechanism appears to satisfy requirements for mediating positive symptoms, how it affects network activity in the ACx and auditory thalamus is unclear. In this competitive renewal application, we propose to analyze abnormal spontaneous activity in neuronal ensembles in the ACx and auditory thalamus in behaving mice. For the ACx, we will use 2-photon imaging through a cranial window, and for the auditory thalamus, we will use a head-attached miniscope (1-photon imaging) or 2-photon imaging through graded index lenses. We will also study the mechanisms underlying age-dependent decline in the expression of miR-338-3p and connect it to the late onset of abnormal synchronicity in the ACx of 22q11DS models. This work will elucidate new mechanisms of the most enigmatic symptoms of SCZ and provide a framework for the development of specific therapeutic interventions to alleviate positive symptoms in patients with this catastrophic disease.