DAVID VOLK, MD, PHD
TRANSLATIONAL NEUROSCIENCE PROGRAM
UNIVERSITY OF PITTSBURGH
Exploring the Relationship Between
Cannabi...
Cannabis Use and Schizophrenia
Associated with worse clinical outcome
 Kavanagh Drugs 2002
Prefrontal cortex-related co...
Endocannabinoid (eCB) System
CB1 receptor is
located on inhibitory
axon terminals
Activation of the CB1
receptor suppres...
Endocannabinoid (eCB) System and Schizophrenia
GABA signaling is already impaired in the PFC in
schizophrenia which contr...
What is the status of eCB signaling in schizophrenia?
Lower CB1 receptor mRNA and protein levels in the PFC in
schizophre...
2-AG: The Brain’s Own Cannabis
2-AG (2-arachidonyloglycerol) is an endogenous
cannabinoid
2-AG is synthesized by diacylg...
Endocannabinoid Signaling Suppresses GABA Release
Subject Demographics
Control Schizophrenia T Value
(df=82)
P Value
N 42 42
Sex 31M/11F 31M/11F
Race 34W/8B 29W/13B
Age (ye...
Project Design
Real-time reverse transcription PCR (quantitative PCR)
RNA isolated from PFC area 9
RNA is reversed tran...
2-AG Synthesizing and Metabolizing Enzymes
DAGLα DAGLβ MGL
ANCOVA F Stat P Value F Stat P Value F Stat P Value
F1,38 .019 ...
Metabolizing Enzyme for Anandamide
FAAH
ANCOVA F Stat P Value
F1,38 1.1 .30
RelativeExpressionLevelinSchiz
Relative Expres...
Group I Metabotropic Glutamate Receptors
mGluR1α mGluR5
ANCOVA F Stat P Value F Stat P Value
F1,38 9.2 .004 3.5 .07
+12.4%...
Summary of Findings
No change in 2-AG or anandamide synthesizing or
metabolizing enzyme mRNA expression levels in
PFC are...
Validation of Results with Additional Primers
Primer Set %
Change
in Schiz
Unpaired (F1,16) Paired (F1,8)
F P F P
mGluR1α_...
Interpreting Elevated mGluR1α mRNA
Expression in Schizophrenia
Elevated signaling through mGluR1α receptors may
increase ...
RGS4 and mGluR1α in Schizophrenia
RGS4 (Regulator of G Protein Signaling) reduces the
duration of signaling from some G p...
RGS4 mRNA Expression in Schizophrenia
ANCOVA F Stat P Value
F1,38 29.4 .000
-16.1%
RelativeExpressionLevelinSchizophrenia
...
Interpreting Elevated mGluR1α mRNA
Expression in Schizophrenia
Are elevated mGluR1α mRNA levels associated with
enhanced ...
Novel Treatment Approaches for Schizophrenia
mGluR1α antagonist may reduce eCB-mediated
suppression of GABA signaling
 m...
Acknowledgements
David Lewis, MD, Director of the Translational
Neuroscience Program
Translational Neuroscience Program ...
Questions and Comments?
Future Studies
Cannabis use during adolescence is a risk factor for
schizophrenia
 Moore Lancet 2007
Mechanism of incre...
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Endocannabinoid Signaling in the Prefrontal Cortex in Schizophrenia

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  • Exploring the biological basis of this important, but poorly understood, interaction between cannabis use and schizophrenia requires knowledge of the neural circuitry that is directly affected by cannabis: the endogenous cannabinoid (eCB) system.
  • Additional markers may be helpful to determine the status of eCB signalingi n schizophrenia. For example, higher signaling through mGluR1a/5 may lead to higher 2-AG levels and excessive suppression of GABA signaling.
  • Endocannabinoid Signaling in the Prefrontal Cortex in Schizophrenia

    1. 1. DAVID VOLK, MD, PHD TRANSLATIONAL NEUROSCIENCE PROGRAM UNIVERSITY OF PITTSBURGH Exploring the Relationship Between Cannabis Use, Cognitive Deficits and Schizophrenia: Role of the Endogenous Cannabinoid System
    2. 2. Cannabis Use and Schizophrenia Associated with worse clinical outcome  Kavanagh Drugs 2002 Prefrontal cortex-related cognitive impairments  Solowoji JAMA 2002 Exacerbates cognitive impairments in schizophrenia  D’Souza BiolPsych 2005
    3. 3. Endocannabinoid (eCB) System CB1 receptor is located on inhibitory axon terminals Activation of the CB1 receptor suppresses the release of GABA
    4. 4. Endocannabinoid (eCB) System and Schizophrenia GABA signaling is already impaired in the PFC in schizophrenia which contributes to cognitive deficits in schizophrenia Cannabis use may worsen cognitive deficits in schizophrenia by aggravating pre-existing deficits in GABA signaling Alterations in eCB signaling may worsen impairments in GABA signaling in schizophrenia
    5. 5. What is the status of eCB signaling in schizophrenia? Lower CB1 receptor mRNA and protein levels in the PFC in schizophrenia (Eggan ArchGenPsych 2008) Knowing the status of eCB signaling requires knowledge of the regulation of the eCB ligands that bind to the CB1 receptor
    6. 6. 2-AG: The Brain’s Own Cannabis 2-AG (2-arachidonyloglycerol) is an endogenous cannabinoid 2-AG is synthesized by diacylglycerol lipase (DAGL) 2-AG is metabolized by monoglyceride lipase (MGL) 2-AG activates CB1 receptors and reduces the release of GABA
    7. 7. Endocannabinoid Signaling Suppresses GABA Release
    8. 8. Subject Demographics Control Schizophrenia T Value (df=82) P Value N 42 42 Sex 31M/11F 31M/11F Race 34W/8B 29W/13B Age (years) 48 ± 13 47 ± 13 0.4 p=0.69 PMI (hours) 17.8 ± 5.9 18.1 ± 8.7 .17 p=0.86 Storage (mo) 97 ± 43 97 ± 46 .02 p=0.98 pH 6.7 ± 0.2 6.6 ± 0.4 1.67 p=.10 RIN 8.3 ± 0.6 8.2 ± 0.7 1.2 p=.23
    9. 9. Project Design Real-time reverse transcription PCR (quantitative PCR) RNA isolated from PFC area 9 RNA is reversed transcribed to cDNA Quantitative PCR performed with SYBR Green and gene- specific primers Gene expression levels normalized to 3 reference genes
    10. 10. 2-AG Synthesizing and Metabolizing Enzymes DAGLα DAGLβ MGL ANCOVA F Stat P Value F Stat P Value F Stat P Value F1,38 .019 .89 .018 .90 .841 .37 Relative Expression Level in Control Subjects RelativeExpressionLevelinSchiz
    11. 11. Metabolizing Enzyme for Anandamide FAAH ANCOVA F Stat P Value F1,38 1.1 .30 RelativeExpressionLevelinSchiz Relative Expression Level in Control Subjects
    12. 12. Group I Metabotropic Glutamate Receptors mGluR1α mGluR5 ANCOVA F Stat P Value F Stat P Value F1,38 9.2 .004 3.5 .07 +12.4% +4.3% RelativeExpressionLevelinSchiz Relative Expression Level in Control Subjects
    13. 13. Summary of Findings No change in 2-AG or anandamide synthesizing or metabolizing enzyme mRNA expression levels in PFC area 9 in schizophrenia.  However, we do not know if changes may be still be present at the protein level (i.e. amount and/or activity of enzyme). Elevated mGluR1α mRNA expression levels in the PFC in schizophrenia.
    14. 14. Validation of Results with Additional Primers Primer Set % Change in Schiz Unpaired (F1,16) Paired (F1,8) F P F P mGluR1α_1 +38.8% 38.5 .000 37.6 .000 mGluR1α_2 +39.9% 39.1 .000 91.3 .000 mGluR1α_3 +30.7% 26.8 .000 57.2 .000
    15. 15. Interpreting Elevated mGluR1α mRNA Expression in Schizophrenia Elevated signaling through mGluR1α receptors may increase 2-AG signaling, resulting in a further deleterious reduction in GABA neurotransmission in the PFC in schizophrenia. Are elevated mGluR1α mRNA levels associated with enhanced signaling through the receptor?  Elevated mGluR1α protein levels (and no change in mGluR5) previously reported in the PFC in schizophrenia (Gupta Synapse 2005).
    16. 16. RGS4 and mGluR1α in Schizophrenia RGS4 (Regulator of G Protein Signaling) reduces the duration of signaling from some G protein coupled receptors, including mGluR1α (Saugstad JNeurosci 1998). Lower RGS4 mRNA levels have been reported in the PFC in schizophrenia (Mirnics MolPsych 2001, Erdely Synapse 2006). Lower RGS4 and higher mGluR1α levels may together further enhance signaling through mGluR1α receptors in the PFC.
    17. 17. RGS4 mRNA Expression in Schizophrenia ANCOVA F Stat P Value F1,38 29.4 .000 -16.1% RelativeExpressionLevelinSchizophrenia Relative Expression Level in Control Subjects *8 pairs previously studied
    18. 18. Interpreting Elevated mGluR1α mRNA Expression in Schizophrenia Are elevated mGluR1α mRNA levels associated with enhanced signaling through the receptor?  Elevated mGluR1α protein levels (and no change in mGluR5) previously reported in the PFC in schizophrenia (Gupta Synapse 2005).  The combination of lower RGS4 and higher mGluR1α levels may together further enhance signaling through mGluR1α receptors in the PFC.
    19. 19. Novel Treatment Approaches for Schizophrenia mGluR1α antagonist may reduce eCB-mediated suppression of GABA signaling  mGluR1α /5 activation induces LTP/LTD of AMPA and NMDA receptors (Ireland and Abraham JNeuroPhys 2009) DAGL inhibitor would reduce suppression of GABA release  Specific for 2-AG and not other eCB ligands
    20. 20. Acknowledgements David Lewis, MD, Director of the Translational Neuroscience Program Translational Neuroscience Program Faculty and Staff Liz Sengupta
    21. 21. Questions and Comments?
    22. 22. Future Studies Cannabis use during adolescence is a risk factor for schizophrenia  Moore Lancet 2007 Mechanism of increased sensitivity to the effects of cannabis during adolescence is not understood Knowledge of the development of the eCB system in the PFC may provide insights into mechanisms that lead to a period of increased sensitivity to cannabis

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