title: Loss of Interneuron-Derived Collagen XIX Leads to a Reduction in Perineuronal Nets in the Mammalian Telencephalon.
abstract: 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.
authors.affiliation: 1 Virginia Tech Carilion Research Institute, Roanoke, VA, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Su
authors.affiliation: 1 Virginia Tech Carilion Research Institute, Roanoke, VA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Cole
authors.affiliation: 1 Virginia Tech Carilion Research Institute, Roanoke, VA, USA.|2 Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA.|3 Department of Pediatrics, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fox
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D024021:Fibril-Associated Collagens; D005786:Gene Expression Regulation / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D037121:Plant Lectins / Q000378:metabolism; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034781:Receptors, N-Acetylglucosamine / Q000378:metabolism; D013687:Telencephalon / Q000166:cytology*
chemical_list: D001426:Bacterial Proteins; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D024021:Fibril-Associated Collagens; D008164:Luminescent Proteins; D037121:Plant Lectins; D011509:Proteoglycans; D012333:RNA, Messenger; D034781:Receptors, N-Acetylglucosamine; C425332:col19a1 protein, mouse; C040129:wisteria lectin; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; D003094:Collagen; D014453:Glucuronosyltransferase; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D010751:Phosphopyruvate Hydratase
keywords: aggrecan; cerebral cortex; collagen; extracellular matrix; hippocampus; perineuronal net