The role of cannabinoid 1 receptor expressing interneurons in behavior.
Schizophrenia is a devastating neurodevelopmental disorder that affects approximately 1% of the population. Reduced expression of the 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of the disease and is encoded by the GAD1 gene. In schizophrenia, GAD67 downregulation occurs in multiple interneuronal subpopulations, including the cannabinoid receptor type 1 positive (CNR1+) cells, but the functional consequences of these disturbances are not well understood. To investigate the role of the CNR1-positive GABA-ergic interneurons in behavioral and molecular processes, we employed a novel, miRNA-mediated transgenic mouse approach. We silenced the Gad1 transcript using a miRNA engineered to specifically target Gad1 mRNA under the control of Cnr1 bacterial artificial chromosome. Behavioral characterization of our transgenic mice showed elevated and persistent conditioned fear associated with an auditory cue and a significantly altered response to an amphetamine challenge. These deficits could not be attributed to sensory deficits or changes in baseline learning and memory. Furthermore, HPLC analyses revealed that Cnr1/Gad1 mice have enhanced serotonin levels, but not dopamine levels in response to amphetamine. Our findings demonstrate that dysfunction of a small subset of interneurons can have a profound effect on behavior and that the GABA-ergic, monoamine, and cannabinoid systems are functionally interconnected. The results also suggest that understanding the function of various interneuronal subclasses might be essential to develop knowledge-based treatment strategies for various mental disorders including schizophrenia and substance abuse.
Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA.
Jacquelyn A
JA
Brown
Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA; Department of Psychiatry, University of Szeged, 6725 Szeged, Hungary.
Szatmár
S
Horváth
Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA.
Krassimira A
KA
Garbett
Neuroscience Graduate Program, Vanderbilt University, Nashville, TN 37232, USA.
Martin J
MJ
Schmidt
Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA.
Monika
M
Everheart
Department of Psychiatry, University of Szeged, 6725 Szeged, Hungary.
Levente
L
Gellért
Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA.
Philip
P
Ebert
Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA; Department of Psychiatry, University of Szeged, 6725 Szeged, Hungary; Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: karoly.mirnics@vanderbilt.edu.
Károly
K
Mirnics
D000661:Amphetamine / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000166:cytology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000502:physiology; D003511:Cyclohexanols / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D055139:Sensory Gating / Q000235:genetics
D000700:Analgesics; D000697:Central Nervous System Stimulants; D003511:Cyclohexanols; D009478:Neuropeptide Y; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000661:Amphetamine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
Amphetamine; Behavior; Cnr1; Dopamine; GAD67; Gad1; Interneuron; Schizophrenia; Serotonin; Transgenic; miRNA