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Myriam Heiman. Vernon, Amanda, Ph. D. Massachusetts Institute of Technology. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences 2021-10-06T19:57:16Z 2021-10-06T19:57:16Z 2019 2019 https://hdl.handle.net/1721.1/132750 1264709193 Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, June, 2019 Cataloged from the PDF version of thesis. Includes bibliographical references (pages 186-208). Schizophrenia is a psychiatric disorder characterized by multiple clusters of symptoms including positive symptoms, such as hallucinations and delusions, negative symptoms, such as decreased motivation and flattened affect, and cognitive symptoms, such as memory impairment and impaired executive function. Currently available antipsychotics mitigate some symptoms of schizophrenia, particularly the positive symptoms, but there is no preventive treatment nor cure after schizophrenia develops. Efforts to generate more effective antipsychotics are made particularly challenging by the fact that the therapeutic effect of currently prescribed antipsychotics is not well understood and the cell type(s) and brain circuits crucial for beneficial effects have not been conclusively identified. Here we show that chronic antipsychotic administration enhances glutamatergic function in the ventral striatum through translational alterations and increased synaptic function. Cell type-specific mRNA profiling on spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways following chronic antipsychotic administration revealed cell type-specific molecular alterations indicating increases in components of the glutamatergic postsynaptic density. Subsequent functional experiments demonstrated the presence of calcium-permeable AMPARs and increased mEPSC frequency following chronic administration of one especially effective antipsychotic, clozapine. Furthermore, we find that striatal astrocytes also respond to chronic antipsychotic treatment with translational alterations promoting synaptogenesis. Together, these data have identified a core molecular signature of increased glutamatergic transmission in the striatum induced by chronic antipsychotic treatment. This work provides evidence that effective antipsychotics address a lack of glutamatergic drive into the striatum in cases of schizophrenia. Additionally, it suggests that drug development efforts seeking improved antipsychotics may benefit by finding compounds that feature an increased glutamatergic drive into the striatum as a core function. by Amanda Vernon. Ph.D. Ph.D. Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences 208 pages eng Massachusetts Institute of Technology MIT theses may be protected by copyright. Please reuse MIT thesis content according to the MIT Libraries Permissions Policy, which is available through the URL provided. http://dspace.mit.edu/handle/1721.1/7582 Brain and Cognitive Sciences. Enhanced striatal glutamatergic function upon chronic antipsychotic action Thesis application/pdf 2021-10-06T19:57:16Z Publication Doctoral Brain unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="9343d161-1927-42a6-97ae-0c1d14b104f0"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>Enhanced striatal glutamatergic function upon chronic antipsychotic action</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2019</PublicationDate> <Authors> <Author> <DisplayName>Vernon, Amanda, Ph. D. Massachusetts Institute of Technology.</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>http://dspace.mit.edu/handle/1721.1/7582</License> <Keyword>Brain and Cognitive Sciences.</Keyword> <Abstract>Schizophrenia is a psychiatric disorder characterized by multiple clusters of symptoms including positive symptoms, such as hallucinations and delusions, negative symptoms, such as decreased motivation and flattened affect, and cognitive symptoms, such as memory impairment and impaired executive function. Currently available antipsychotics mitigate some symptoms of schizophrenia, particularly the positive symptoms, but there is no preventive treatment nor cure after schizophrenia develops. Efforts to generate more effective antipsychotics are made particularly challenging by the fact that the therapeutic effect of currently prescribed antipsychotics is not well understood and the cell type(s) and brain circuits crucial for beneficial effects have not been conclusively identified. Here we show that chronic antipsychotic administration enhances glutamatergic function in the ventral striatum through translational alterations and increased synaptic function. Cell type-specific mRNA profiling on spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways following chronic antipsychotic administration revealed cell type-specific molecular alterations indicating increases in components of the glutamatergic postsynaptic density. Subsequent functional experiments demonstrated the presence of calcium-permeable AMPARs and increased mEPSC frequency following chronic administration of one especially effective antipsychotic, clozapine. Furthermore, we find that striatal astrocytes also respond to chronic antipsychotic treatment with translational alterations promoting synaptogenesis. Together, these data have identified a core molecular signature of increased glutamatergic transmission in the striatum induced by chronic antipsychotic treatment. This work provides evidence that effective antipsychotics address a lack of glutamatergic drive into the striatum in cases of schizophrenia. Additionally, it suggests that drug development efforts seeking improved antipsychotics may benefit by finding compounds that feature an increased glutamatergic drive into the striatum as a core function.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>