Su et al. describe how a proteolytic fragment of collagen XIX may protect the brain from schizophrenia by promoting the formation of inhibitory synapses.
The collagen family of extracellular matrix proteins performs numerous functions in the brain, and mutations in several family members cause neurological diseases in humans. Deletion of the gene encoding collagen XIX, for example, may cause familial schizophrenia, though how this unconventional, nonfibrillar collagen promotes normal brain function is unknown.
Su et al. examined collagen XIX–deficient mice and found that they displayed a number of schizophrenia-related symptoms, including an abnormal startle response and an increased susceptibility to seizures. Schizophrenia has previously been linked to defects in a particular type of interneuron that dampens neuronal activity in the brain’s cortex by forming inhibitory synapses with the cell bodies of other neurons. These inhibitory synapses were lost in collagen XIX–deficient mice although, surprisingly, wild-type animals mainly express collagen XIX in other types of cortical interneuron, suggesting that the protein promotes synaptogenesis via a paracrine mechanism.
Like other unconventional collagens, collagen XIX can be cleaved by extracellular proteases to generate a small, C-terminal signaling peptide called a matricryptin. Su et al. found that this peptide was sufficient to rescue the formation of inhibitory synapses in neuronal cultures prepared from collagen XIX–deficient mice, apparently by binding and activating the integrin adhesion receptor α5β1.
Senior author Michael Fox now wants to learn more about how collagen XIX’s matricryptin fragment promotes synaptogenesis, and to investigate whether the peptide holds any therapeutic potential for schizophrenia patients.