Cannabis use by individuals with, or at risk for, schizophrenia is increasingly recognized as a major public health concern. For example, cannabis use is linked to an increased risk for developing schizophrenia and poorer long-term outcomes in individuals who already have schizophrenia. Cannabis use also induces prefrontal cortex (PFC)-related cognitive impairments similar to those seen in schizophrenia. Interestingly, deficits in RFC GABA neurons may lead to cognitive problems in schizophrenia, and cannabis reduces GABA signaling by activating the CB1 receptor. Thus, one potential link between cannabis use and cognitive impairments in schizophrenia may involve an interaction of deficits in the RFC GABA system. Direct investigations of the eCB system in schizophrenia may help further clarify the biological basis for the negative consequences of cannabis use in schizophrenia. For example, determining whether the recently reported finding of lower RFC CB1 receptor levels in schizophrenia reflects a deficiency in eCB signaling, or, conversely, a downregulation of CB1 receptor levels in response to excessive eCB signaling requires knowledge of the eCB ligand (2-AG) that binds to the CB1 receptor. Furthermore, why is the eCB system altered in schizophrenia in the first place? One possibility is that alterations in eCB signaling in schizophrenia are pathogenetically downstream to impairments in GABA synthesis.Therefore, the first two aims will determine whether (and how) the mRNA and protein levels for the synthesizing and metabolizing enzymes (diacylglycerol lipase and monoglyceride lipase) for 2-AG are changed in the RFC in schizophrenia using quantitative PCR, in situ hybridization, Western blots, and immunocytochemistry.
The third aim will use in vivo injections of lentiviral vectors expressing siRNA against the GABA synthesizing enzyme, GAD67, and determine the effects on markers of eCB signaling. The training goal of this application is to obtain the necessary research skills to become an independent investigator who tests pathogenetic hypotheses involving cortical circuitry abnormalities in schizophrenia by combining postmortem human brain tissue studies with cell-type specific genetic manipulations in animal models.

Public Health Relevance

These studies will provide insight into potential abnormalities in the brain's own cannabis system in schizophrenia and may help identify new treatment possibilities for the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH084016-05
Application #
8393503
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chavez, Mark
Project Start
2009-04-01
Project End
2014-06-30
Budget Start
2013-01-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$171,515
Indirect Cost
$12,705
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Volk, David W; Eggan, Stephen M; Horti, Andrew G et al. (2014) Reciprocal alterations in cortical cannabinoid receptor 1 binding relative to protein immunoreactivity and transcript levels in schizophrenia. Schizophr Res 159:124-9
Siegel, Benjamin I; Sengupta, Elizabeth J; Edelson, Jessica R et al. (2014) Elevated viral restriction factor levels in cortical blood vessels in schizophrenia. Biol Psychiatry 76:160-7
Volk, David W; Edelson, Jessica R; Lewis, David A (2014) Cortical inhibitory neuron disturbances in schizophrenia: role of the ontogenetic transcription factor Lhx6. Schizophr Bull 40:1053-61
Curley, Allison A; Eggan, Stephen M; Lazarus, Matt S et al. (2013) Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: implications for schizophrenia. Neurobiol Dis 50:179-86
Volk, David W; Siegel, Benjamin I; Verrico, Christopher D et al. (2013) Endocannabinoid metabolism in the prefrontal cortex in schizophrenia. Schizophr Res 147:53-7
Volk, D W; Lewis, D A (2013) Prenatal ontogeny as a susceptibility period for cortical GABA neuron disturbances in schizophrenia. Neuroscience 248:154-64
Volk, David W; Radchenkova, Polina V; Walker, Erin M et al. (2012) Cortical opioid markers in schizophrenia and across postnatal development. Cereb Cortex 22:1215-23
Curley, Allison A; Arion, Dominique; Volk, David W et al. (2011) Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features. Am J Psychiatry 168:921-9
Volk, David W; Eggan, Stephen M; Lewis, David A (2010) Alterations in metabotropic glutamate receptor 1* and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. Am J Psychiatry 167:1489-98