Sensorimotor gating deficits in transgenic mice expressing a constitutively active form of Gs alpha.
Schizophrenia is a complex disorder characterized by wide-ranging cognitive impairments, including deficits in learning as well as sensory gating. The causes of schizophrenia are unknown, but alterations in intracellular G-protein signaling pathways are among the molecular changes documented in patients with schizophrenia. Using the CaMKIIalpha promoter to drive expression in neurons within the forebrain, we have developed transgenic mice that express a constitutively active form of G(s)alpha (G(s)alpha(*)), the G protein that couples receptors such as the D(1) and D(5) dopamine receptors to adenylyl cyclase. We have also generated mice in which the CaMKIIalpha promoter drives expression of a dominant-negative form of protein kinase A, R(AB). Here, we examine startle responses and prepulse inhibition of the startle reflex (PPI) in these G(s)alpha(*) and R(AB) transgenic mice. G(s)alpha(*) transgenic mice exhibited selective deficits in PPI, without exhibiting alterations in the startle response, whereas no deficit in startle or PPI was found in the R(AB) transgenic mice. Thus, overstimulation of the cAMP/PKA pathway disrupts PPI, but the cAMP/PKA pathway may not be essential for sensorimotor gating. G(s)alpha(*) transgenic mice may provide an animal model of certain endophenotypes of schizophrenia, because of the similarities between them and patients with schizophrenia in G-protein function, hippocampus-dependent learning, and sensorimotor gating.
Gould
Thomas J
TJ
Department of Psychology, Temple University, Weiss Hall, Philadelphia, PA, USA.
Bizily
Scott P
SP
Tokarczyk
Jan
J
Kelly
Michele P
MP
Siegel
Steven J
SJ
Kanes
Stephen J
SJ
Abel
Ted
T
D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011597:Psychomotor Performance / Q000502:physiology*; D013216:Reflex, Startle / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism
D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs