Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing Galphas, a G-protein subunit genetically linked to schizophrenia.
Schizophrenia is a widespread psychiatric disorder, affecting 1% of people. Despite this high prevalence, schizophrenia is not well treated because of its enigmatic developmental origin. We explore here the developmental etiology of endophenotypes associated with schizophrenia using a regulated transgenic approach in mice. Recently, a polymorphism that increases mRNA levels of the G-protein subunit Galphas was genetically linked to schizophrenia. Here we show that regulated overexpression of Galphas mRNA in forebrain neurons of mice is sufficient to cause a number of schizophrenia-related phenotypes, as measured in adult mice, including sensorimotor gating deficits (prepulse inhibition of acoustic startle, PPI) that are reversed by haloperidol or the phosphodiesterase inhibitor rolipram, psychomotor agitation (hyperlocomotion), hippocampus-dependent learning and memory retrieval impairments (hidden water maze, contextual fear conditioning), and enlarged ventricles. Interestingly, overexpression of Galphas during development plays a significant role in some (PPI, spatial learning and memory and neuroanatomical deficits) but not all of these adulthood phenotypes. Pharmacological and biochemical studies suggest the Galphas-induced behavioral deficits correlate with compensatory decreases in hippocampal and cortical cyclic AMP (cAMP) levels. These decreases in cAMP may lead to reduced activation of the guanine exchange factor Epac (also known as RapGEF 3/4) as stimulation of Epac with the select agonist 8-pCPT-2'-O-Me-cAMP increases PPI and improves memory in C57BL/6J mice. Thus, we suggest that the developmental impact of a given biochemical insult, such as increased Galphas expression, is phenotype specific and that Epac may prove to be a novel therapeutic target for the treatment of both developmentally regulated and non-developmentally regulated symptoms associated with schizophrenia.
Kelly
M P
MP
Department of Biology, University of Pennsylvania, Monmouth Junction, NJ 08852, USA. kellym22@wyeth.com
Stein
J M
JM
Vecsey
C G
CG
Favilla
C
C
Yang
X
X
Bizily
S F
SF
Esposito
M F
MF
Wand
G
G
Kanes
S J
SJ
Abel
T
T
D000111:Acetylcysteine / Q000819:agonists / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D000161:Acoustic Stimulation; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics* / Q000473:pathology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004917:Erythromycin / Q000819:agonists / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D006220:Haloperidol / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011601:Psychophysics; D013216:Reflex, Startle / Q000235:genetics; D020889:Rolipram / Q000494:pharmacology; D013997:Time Factors
C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; D014150:Antipsychotic Agents; D010726:Phosphodiesterase Inhibitors; D004917:Erythromycin; C057513:erythromycin propionate-N-acetylcysteinate; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs; D006220:Haloperidol; D020889:Rolipram; D000111:Acetylcysteine