Enhanced striatal glutamatergic function upon chronic antipsychotic action

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.

Name thesis:degree_name

Doctoral

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2019

Author dc:creator

• Vernon, Amanda, Ph. D. Massachusetts Institute of Technology.

Advisor dc:contributor.advisor

• Myriam Heiman.

• Brain and Cognitive Sciences.

Statement dc:rights

• 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.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/132750

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/132750