Inhibitor of neuronal connectivity linked to schizophrenia susceptibility and cognitive dysfunction
The present invention relates to methods and compositions for enhancing neuronal connectivity. It is based, at least in part, on the discovery of a protein, termed “Mirta22,” that inhibits the formation of structures which create connections between neurons. It is further based, in part, on the discovery that inhibiting Mirta22 activity by short hairpin RNA was able to restore these structures. Mirta22 was discovered in experiments relating to 22q11 microdeletions, which have been linked to schizophrenia. Accordingly, the present invention provides for methods of treating schizophrenia comprising administering an agent that inhibits Mirta22 activity. It may also be used in the treatment of other disorders that would benefit from enhanced neural connectivity, including learning and memory disorders.
1. A method of increasing neuronal connectivity in a human subject with schizophrenia, comprising administering to said subject a therapeutic amount of an agent that inhibits Mirta22 activity, wherein Mirta22 is encoded by a nucleic acid comprising a sequence of SEQ ID NO:3, and where said amount increases connectivity between neurons in an in vitro assay, as determined by an increase in the number of primary dendrites, an increase in dendrite spine density, or a combination thereof.
2. The method of claim 1 , where the agent is selected from the group consisting of antisense RNA comprising a sequence complementary to the Mirta22 mRNA; and RNAi comprising a sequence complementary to the Mirta22 mRNA.
3. The method of claim 2 , wherein the RNAi comprises shRNA comprising a sequence complementary to the Mirta22 mRNA.