Sensorimotor Gating Deficits in Transgenic Mice Expressing a Constitutively Active Form of Gsα

Gould, Thomas J.; Bizily, Scott P; Tokarczyk, Jan; Kelly, Michy P.; Siegel, Steven J.; Kanes, Stephen; Abel, Ted

doi:10.1038/sj.npp.1300309

Cited by 34 publications

(28 citation statements)

References 60 publications

(76 reference statements)

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“…Given that inhibition of PKA within the forebrain is not sufficient to decrease PPI (Gould et al, 2004), and in fact rescues the transgenic deficits, the effect of decreased cAMP signaling on PPI is likely mediated through decreased signaling of other downstream targets of cAMP, such as Epac or cyclic nucleotide-gated channels. Future studies will examine possible mechanisms by which PKA mediates the effect of Gas* expression on PPI and cortical cAMP deficits.…”

Section: Discussionmentioning

confidence: 99%

“…For experiments examining coexpression of Gas* and R(AB), a hemizygous Gas* transgenic mouse was mated to a hemizygous R(AB) transgenic mouse (each backcrossed to C57BL/6J N10-N13), and all offspring were compared (WT, Gas* transgenic, R(AB) transgenic, Gas*, and R(AB) bitransgenic). As described previously (Wand et al, 2001;Gould et al, 2004), Gas* transgenic mice express an isoform of the Gas* that is constitutively active because of a point mutation (Q227L) that prevents hydrolysis of bound GTP, resulting in significantly increased basal adenylyl cyclase activity (Wand et al, 2001). This transgene is expressed in addition to the endogenous genomic copy of Gas, which we have verified remains functional (as indicated by increased adenylyl cyclase activity in response to GTPgS stimulation; data not shown).…”

Section: Subjectsmentioning

confidence: 99%

“…Startle responses to acoustic stimuli and inhibition of startle responses because of presentation of a nonstartling acoustic prepulse were measured as described previously (protocol 2; Gould et al, 2004), except that background was set to 68 dB. Briefly, startle responses were measured by an accelerometer in response to acoustic stimuli delivered by a white noise generator (4-19 kHz; SR-Lab, San Diego, CA).…”

Section: Ppimentioning

confidence: 99%

“…Further, a polymorphism, which results in increased mRNA expression of Gas (Frey et al, 2005), has recently been genetically linked to schizophrenia (Minoretti et al, 2006). Interestingly, transgenic mice expressing a constitutively active isoform of Gas (Gas*) show decreased PPI (Gould et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Kelly

Isiegas

Cheung

et al. 2006

Neuropsychopharmacol

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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 Gas (Gas*) 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 Gas* 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 Gas* increases cAMP levels in the striatum. Suprisingly, however, Gas* 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 Gas* on PPI because Rp-cAMPS decreases PPI in C57BL/ 6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Gas* mice and the cPDE inhibitor rolipram also rescues PPI deficits of Gas* mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Gas* 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 Gas*. We conclude that expression of Gas* within forebrain neurons causes PPI deficits because of a PKAdependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.

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Section: Discussionmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

Section: Ppimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Kelly

Isiegas

Cheung

et al. 2006

Neuropsychopharmacol

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“…Animals received either haloperidol (n=16) or blank implants (n=16). Mice were then tested at 21 days after implantation using previously described protocols for PPI (Gould et al 2004). Each animal was tested after an injection of either vehicle (n=16) or D-amphetamine (Sigma) 10 mg/kg i.p.…”

Section: In Vivo Studiesmentioning

confidence: 99%

Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits

et al. 2006

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. Pharmacokinetic and behavioral characterization of a longterm antipsychotic delivery system in rodents and rabbits. Retrieved from http://repository.upenn.edu/mse_papers/122Pharmacokinetic and behavioral characterization of a longterm antipsychotic delivery system in rodents and rabbits AbstractRationale: Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel longterm delivery systems.Objectives: The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits.Materials and methods: Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits.Results: Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits. Conclusions:The current study suggests that implantable formulations are a viable approach to providing longterm delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a degree of reversibility not available with depot formulations. AbstractRationale Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel long-term delivery systems. Objectives The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits. Materials and methods Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits. Results Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits. Conclusions The current study suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a ...

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Event-Related Potentials (ERPs) in the Study of Schizophrenia: How Preclinical ERP Studies have Contributed to our Understanding of Schizophrenia

Phillips¹,

Maxwell²,

Ehrlichman³

et al. 2009

Handbook of Neurochemistry and Molecular Neurobiology

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Sensorimotor Gating Deficits in Transgenic Mice Expressing a Constitutively Active Form of Gsα

Cited by 34 publications

References 60 publications

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits

Event-Related Potentials (ERPs) in the Study of Schizophrenia: How Preclinical ERP Studies have Contributed to our Understanding of Schizophrenia

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