Normally, dendritic size is established prior to adolescence and then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wild-type KAL. In mice containing this missense mutation at the endogenous locus, there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Spine density per unit length of dendrite is unaffected. Early adult mice with these structural deficits exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease.

通常，树突大小在青春期之前就已确定，然后由于生长和回缩途径之间的稳态平衡而在成年期保持相对恒定。然而，精神分裂症的特点是大脑皮层灰质体积加速减少，并在青春期出现临床症状，死后多个皮层区域发现第 3 层锥体神经元树突长度、复杂性和棘密度减少。 GTPase RhoA 的 Nogo 受体 1 (NGR1) 激活是限制大脑皮层树突生长的主要途径。我们发现 NGR1 途径受 OMGp 刺激，并且需要 Rho 鸟嘌呤核苷酸交换因子 Kalirin-9 (KAL9)。使用基因编码的 RhoA 传感器，我们证明了在精神分裂症队列中发现的Kalrn中自然发生的错义突变 KAL-PT，与野生型 KAL 相比，使神经元树突中的 RhoA 激活增强。在内源基因座含有这种错义突变的小鼠中，初级听觉皮层中第 3 层锥体神经元的树突长度和复杂性在青少年时期出现减少。每单位长度树突的脊柱密度不受影响。具有这些结构缺陷的早期成年小鼠表现出对短间隙持续时间的检测能力受损。这些发现提供了一种疾病的神经精神病学模型，捕捉了轻微的遗传脆弱性如何与正常发育过程相互作用，从而导致病理仅在青春期左右出现。遗传易感性和正常青少年发育之间的相互作用，两者都具有固有的个体变异性，可能导致人类神经精神疾病表型的异质性。