ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2007
Constitutive activation of Galphas within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed.
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- Brain and eye involvement in McCune-Albright Syndrome: clinical and translational insights.Frontiers in endocrinology · 2023Review
- Forebrain-specific conditional calcineurin deficiency induces dentate gyrus immaturity and hyper-dopaminergic signaling in mice.Molecular brain · 2022Article
- PET Imaging of Phosphodiesterase-4 Identifies Affected Dysplastic Bone in McCune-Albright Syndrome, a Genetic Mosaic Disorder.Journal of nuclear medicine : official publication, Society of Nuclear Medicine · 2020Article
- Cholinergic neurotransmission in the basolateral amygdala during cued fear extinction.Neurobiology of stress · 2020Article
- Phosphodiesterases PDE2A and PDE10A both change mRNA expression in the human brain with age, but only PDE2A changes in a region-specific manner with psychiatric disease.Cellular signalling · 2020Article
- Therapeutic targeting of 3',5'-cyclic nucleotide phosphodiesterases: inhibition and beyond.Nature reviews. Drug discovery · 2019Review
- Cyclic nucleotide phosphodiesterases: potential therapeutic targets for alcohol use disorder.Psychopharmacology · 2018Review
- Cyclic nucleotide signaling changes associated with normal aging and age-related diseases of the brain.Cellular signalling · 2018Review
- Dendritic diameter influences the rate and magnitude of hippocampal cAMP and PKA transients during β-adrenergic receptor activation.Neurobiology of learning and memory · 2017Article
- Phosphodiesterase 11A (PDE11A), Enriched in Ventral Hippocampus Neurons, is Required for Consolidation of Social but not Nonsocial Memories in Mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2016Article
- Growth arrest specific gene 7 is associated with schizophrenia and regulates neuronal migration and morphogenesis.Molecular brain · 2016Article
- Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and 'Schizophrenia-Like Behaviors' in Mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2016Article
- Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.Frontiers in behavioral neuroscience · 2016Article
- Mouse Model of Chromosome 15q13.3 Microdeletion Syndrome Demonstrates Features Related to Autism Spectrum Disorder.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Sensorimotor gating is disrupted by acute but not chronic systemic exposure to caffeine in mice.Psychopharmacology · 2014Article
- The role of PKC signaling in CRF-induced modulation of startle.Psychopharmacology · 2013Article
- Threat bias in mice with inactivating mutations of Prkar1a.Neuroscience · 2013Article
- Antipsychotic induced alteration of growth and proteome of rat neural stem cells.Neurochemical research · 2012Article
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Authors and funding
13 authors.
Funding
Abstract
Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Galphas (Galphas(*)) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Galphas(*) causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Galphas(*) increases cAMP levels in the striatum. Suprisingly, however, Galphas(*) mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Galphas(*) on PPI because Rp-cAMPS decreases PPI in C57BL/6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Galphas(*) mice and the cPDE inhibitor rolipram also rescues PPI deficits of Galphas(*) mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Galphas(*) mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Galphas(*). We conclude that expression of Galphas(*) within forebrain neurons causes PPI deficits because of a PKA-dependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.
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