Loss of Interneuron-Derived Collagen XIX Leads to a Reduction in Perineuronal Nets in the Mammalian Telencephalon.
Loss of Interneuron-Derived Collagen XIX Leads to a Reduction in Perineuronal Nets in the Mammalian Telencephalon.
复制标题
DOI：
10.1177/1759091416689020
复制
发表时间：
2017-02
期刊：
影响因子：
4.7
通讯作者：
Fox MA
中科院分区：
文献类型：
--
作者：
Su J;Cole J;Fox MA
神经元周网（PNN）是细胞外糖蛋白的格子状超分子组装体，围绕哺乳动物端脑中神经元细胞体的子集。PNN出现在大脑发育的关键时期结束时，限制了成年大脑中的神经元可塑性，并且在各种复杂的大脑疾病中丢失，包括精神分裂症。PNNs和精神分裂症之间的联系使我们质疑与精神分裂症相关的神经元表达的细胞外基质（ECM）分子是否有助于组装这些专门的超分子ECM组件。我们专注于胶原蛋白XIX-一个小的，非纤维胶原蛋白表达的亚群的端脑中间神经元。编码胶原蛋白XIX的区域的遗传改变与家族性精神分裂症相关，小鼠中这种胶原蛋白的丢失导致抑制性突触改变、癫痫发作和获得精神分裂症相关行为。在这里，我们证明，胶原蛋白XIX的损失也导致端脑PNN的减少。PNN的损失伴随着聚集蛋白聚糖（Acan）水平的降低，聚集蛋白聚糖是PNN的主要成分。尽管胶原蛋白XIX缺陷小鼠（col 19 a1 −/−）中PNN成分的水平降低，但我们未能检测到编码这些ECM分子的基因表达降低。相反，我们发现了一个广泛的上调细胞外蛋白酶能够裂解Acan和其他PNN成分在col 19 a1 −/−脑。总之，这些结果表明胶原蛋白XIX的损失加速PNN降解的机制，并且它们确定了胶原蛋白XIX的损失可能导致复杂脑疾病的新机制。
Perineuronal nets (PNNs) are lattice-like supramolecular assemblies of extracellular glycoproteins that surround subsets of neuronal cell bodies in the mammalian telencephalon. PNNs emerge at the end of the critical period of brain development, limit neuronal plasticity in the adult brain, and are lost in a variety of complex brain disorders diseases, including schizophrenia. The link between PNNs and schizophrenia led us to question whether neuronally expressed extracellular matrix (ECM) molecules associated with schizophrenia contribute to the assembly of these specialized supramolecular ECM assemblies. We focused on collagen XIX—a minor, nonfibrillar collagen expressed by subsets of telencephalic interneurons. Genetic alterations in the region encoding collagen XIX have been associated with familial schizophrenia, and loss of this collagen in mice results in altered inhibitory synapses, seizures, and the acquisition of schizophrenia-related behaviors. Here, we demonstrate that loss of collagen XIX also results in a reduction of telencephalic PNNs. Loss of PNNs was accompanied with reduced levels of aggrecan (Acan), a major component of PNNs. Despite reduced levels of PNN constituents in collagen XIX-deficient mice (col19a1−/−), we failed to detect reduced expression of genes encoding these ECM molecules. Instead, we discovered a widespread upregulation of extracellular proteases capable of cleaving Acan and other PNN constituents in col19a1−/− brains. Taken together, these results suggest a mechanism by which the loss of collagen XIX speeds PNN degradation and they identify a novel mechanism by which the loss of collagen XIX may contribute to complex brain disorders.