Calcium-sensitive adenylyl cyclases in depression and anxiety: behavioral and biochemical consequences of isoform targeting.
BACKGROUND
Adenylyl cyclases (ACs) represent a diverse family of enzymes responsible for the generation of cyclic adenosine monophosphate (cAMP), a key intracellular second messenger. The Ca(2+)/calmodulin-stimulated AC1 and AC8 isoforms as well as the calcium-inhibited AC5 isoform are abundantly expressed within limbic regions of the central nervous system. This study examines the contribution of these AC isoforms to emotional behavior.


METHODS
Male and female AC1/8 double knockout mice (DKO) and AC5 knockout mice (AC5KO) were examined on a series of standard laboratory assays of emotionality. Mice were also assayed for hippocampal cell proliferation and for changes in brain-derived neurotrophic factor signaling in the nucleus accumbens, amygdala, and hippocampus, three forebrain structures involved in the regulation of mood and affect.


RESULTS
The AC5KO mice showed striking anxiolytic and antidepressant phenotypes on standard behavioral assays. In contrast, AC1/8 DKO mice were hypoactive, exhibited diminished sucrose preference, and displayed alterations in neurotrophic signaling, generally consistent with a prodepressant phenotype. Neither line of mice displayed alterations in hippocampal cell proliferation.


CONCLUSIONS
These data illustrate the complex manner in which Ca(2+)/calmodulin-stimulated ACs contribute to emotional behavior. In addition, they support the possibility that a selective AC5 antagonist would be of therapeutic value against depression and anxiety disorders.
Krishnan
Vaishnav
V
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Graham
Ami
A
Mazei-Robison
Michelle S
MS
Lagace
Diane C
DC
Kim
Kyoung-Shim
KS
Birnbaum
Shari
S
Eisch
Amelia J
AJ
Han
Pyung-Lim
PL
Storm
Daniel R
DR
Zachariou
Venetia
V
Nestler
Eric J
EJ
D000262:Adenylyl Cyclases / Q000145:classification / Q000172:deficiency / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation; D003863:Depression / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005518:Food Preferences / Q000502:physiology; D006185:Habituation, Psychophysiologic / Q000235:genetics; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D013395:Sucrose; D013550:Swimming
D019208:Brain-Derived Neurotrophic Factor; D013395:Sucrose; D000262:Adenylyl Cyclases; D001973:Bromodeoxyuridine; D002118:Calcium