Antipsychotics that antagonize G-protein coupled, dopaminergic receptors alleviate the symptoms of schizophrenia. Prolonged treatment with antipsychotics 'remodels'circuits of the prefrontal cortex and striatum, ameliorating the symptoms of the disease. Our central hypothesis is that this remodeling depends upon the ability of antipsychotics to trigger cell-type specific adaptations in the synaptic connectivity, dendritic architecture and intrinsic excitability of striatal and cortical neurons. Dysregulation of these key sub-cellular regions is likely to be a central factor in schizophrenia and provides an obvious linkage to glutamatergic determinants in the disease. Yet, little is known about how antipsychotics and antipsychotic-sensitive receptors influence dendritic electrogenesis, synaptic integration and plasticity in functionally relevant subpopulations of striatal and PFC neurons. The central goal of the project is to help fill this gap in our understanding, but, there are obstacles to success. One is that the neurons within both the striatum and PFC are heterogeneous. Another major obstacle is the inaccessibility of dendritic regions to physiological study. This proposal takes advantage of BAC transgenic mice, the development of two photon laser scanning microscopy and two photon laser uncaging to overcome these obstacles. These approaches will be used in conjunction with electrophysiological, pharmacological and molecular strategies that complement the other Projects in this Conte Center to pursue three Specific Aims: 1) To characterize the impact of antipsychotic treatment on somatodendritic excitability and morphology of the two principal cell types in the striatum: striatonigral and striatopallidal medium spiny neurons (MSNs);2) To characterize the impact of antipsychotic treatment on the properties of synapses formed by the two principal inputs to striatal MSNs from the cerebral cortex and thalamus;3) To characterize the impact of antipsychotic treatment on the somatodendritic morphology and excitability of identified subsets of prelimbic/infralimbic (PL/IL) cortex pyramidal neurons.

Public Health Relevance

to public health: Schizophrenia is a debilitating psychiatric disorder affecting ~1 % of the population. The successful pursuit of the proposed aims will provide new insights into the mechanism of antipsychotic action in neurons of the prefrontal cortex and striatum, creating an avenue for new treatment development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH090963-05
Application #
8705024
Study Section
Special Emphasis Panel (ZMH1-ERB-M)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$257,400
Indirect Cost
Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Milosevic, Ana; Liebmann, Thomas; Knudsen, Margarete et al. (2016) Cell- and region-specific expression of depression-related protein p11 (S100a10) in the brain. J Comp Neurol :
Xu, Jian; Kurup, Pradeep; Azkona, Garikoitz et al. (2016) Down-regulation of BDNF in cell and animal models increases striatal-enriched protein tyrosine phosphatase 61 (STEP61 ) levels. J Neurochem 136:285-94
Rapanelli, Maximiliano; Frick, Luciana R; Horn, Kyla D et al. (2016) The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons. J Biol Chem 291:21042-21052
Uematsu, Ken; Heiman, Myriam; Zelenina, Marina et al. (2015) Protein kinase A directly phosphorylates metabotropic glutamate receptor 5 to modulate its function. J Neurochem 132:677-86
Wang, Hong; Warner-Schmidt, Jennifer; Varela, Santiago et al. (2015) Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice. Proc Natl Acad Sci U S A 112:9745-50
Snyder, Gretchen L; Vanover, Kimberly E; Zhu, Hongwen et al. (2015) Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl) 232:605-21
Plattner, Florian; Hayashi, Kanehiro; Hernández, Adan et al. (2015) The role of ventral striatal cAMP signaling in stress-induced behaviors. Nat Neurosci 18:1094-100
Nakajima, Miho; Görlich, Andreas; Heintz, Nathaniel (2014) Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons. Cell 159:295-305
Dietz, David M; Kennedy, Pamela J; Sun, Haosheng et al. (2014) ýýFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes. Neuropsychopharmacology 39:538-44
Meyer, Douglas A; Torres-Altoro, Melissa I; Tan, Zhenjun et al. (2014) Ischemic stroke injury is mediated by aberrant Cdk5. J Neurosci 34:8259-67

Showing the most recent 10 out of 37 publications