Phosphodiesterase Type 4 Inhibition Does Not Restore Ocular Dominance Plasticity in a Ferret Model of Fetal Alcohol Spectrum Disorders

Krahe, Thomas E.; Paul, Arco P.; Medina, Alexandre E.

doi:10.1111/j.1530-0277.2009.01114.x

Cited by 5 publications

(4 citation statements)

References 49 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, while cross talks between the cascades exist it is safe to say the CREB and SRF can be preferentially activated by cAMP and cGMP respectively. Recently, we discovered that, contrary to what was observed with vinpocetine, Rolipram, a PDE type 4 inhibitor failed to restore OD plasticity in the ferret model of FASD (Krahe et al, 2010). Since Rolipram increases only cAMP levels and not cGMP, one may suggest that the restoration of plasticity seen earlier is due to SRF activation.…”

Section: Introductionmentioning

confidence: 76%

Overexpression of Serum Response Factor Restores Ocular Dominance Plasticity in a Model of Fetal Alcohol Spectrum Disorders

Paul¹,

Pohl-Guimarães²,

Krahe³

et al. 2010

J. Neurosci.

View full text Add to dashboard Cite

Neuronal plasticity deficits underlie many of the neurobehavioral problems seen in fetal alcohol spectrum disorders (FASD). Recently, we showed that third trimester alcohol exposure leads to a persistent disruption in ocular dominance (OD) plasticity. For instance, a few days of monocular deprivation results in a robust reduction of cortical regions responsive to the deprived eye in normal animals, but not in ferrets exposed early to alcohol. This plasticity deficit can be reversed if alcohol-exposed animals are treated with a phosphodiesterase type 1 (PDE1) inhibitor during the period of monocular deprivation. PDE1 inhibition can increase cAMP and cGMP levels, activating transcription factors such as the cAMP response element binding protein (CREB) and the serum response factor (SRF). SRF is important for many plasticity processes such as LTP, LTD, spine motility, and axonal pathfinding. Here we attempt to rescue OD plasticity in alcohol-treated ferrets using a Sindbis viral vector to express a constitutively active form of SRF during the period of monocular deprivation. Using optical imaging of intrinsic signals and single-unit recordings, we observed that overexpression of a constitutively active form of SRF, but neither its dominant-negative nor GFP, restored OD plasticity in alcohol-treated animals. Surprisingly, this restoration was observed throughout the extent of the primary visual cortex and most cells infected by the virus were positive for GFAP rather than NeuN. This finding suggests that overexpression of SRF in astrocytes may reduce the deficits in neuronal plasticity seen in models of FASD.

show abstract

Section: Introductionmentioning

confidence: 76%

Overexpression of Serum Response Factor Restores Ocular Dominance Plasticity in a Model of Fetal Alcohol Spectrum Disorders

Paul¹,

Pohl-Guimarães²,

Krahe³

et al. 2010

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Inhibition of PDE1 by vinpocetine reversed alcohol exposure-related cortical deficits, rescuing ocular dominance plasticity in ferrets and mice (Lantz, Wang, & Medina, 2012; Medina, Krahe, & Ramoa, 2006) and preventing Morris water maze acquisition impairments in rats (Filgueiras, Krahe, & Medina, 2010). Similar improvement of fetal alcohol-related deficits in ocular dominance plasticity can be generated by co-administration of inhibitors to PDE4 and PDE5, but not by treatment with either inhibitor alone (Krahe, Paul, & Medina, 2010; Lantz et al, 2012), implying that PDE1 inhibitors improve fetal alcohol-related pathology through coordinated elevations in cAMP and cGMP. It is of interest for future investigations to determine whether PDE1 inhibitors similarly reduce cognitive deficits due to excessive alcohol consumption in adulthood, as well as whether PDE1 plays a role in patterning alcohol intake, a function now well established for PDE4.…”

Section: Phosphodiesterase Regulation Of Alcohol Intakementioning

confidence: 90%

Phosphodiesterase regulation of alcohol drinking in rodents

Logrip

2015

Alcohol

View full text Add to dashboard Cite

Alcohol use disorders are chronically relapsing conditions characterized by persistent drinking despite the negative impact on one’s life. The difficulty of achieving and maintaining sobriety suggests that current treatment options fail to fully address the underlying causes of alcohol use disorders, and thus identifying additional pathways controlling alcohol consumption may uncover novel targets for medication development to improve treatment options. One family of proteins recently implicated in the regulation of alcohol consumption is the cyclic nucleotide phosphodiesterases (PDEs). As an integral component in the regulation of the second messengers cyclic AMP and cyclic GMP, and thus their cognate signaling pathways, PDEs present intriguing targets for pharmacotherapies to combat alcohol use disorders. As activation of cAMP/cGMP-dependent signaling cascades can dampen alcohol intake, PDE inhibitors may provide a novel target for reducing excessive alcohol consumption, as has been proposed for PDE4 and PDE10A. This review highlights preclinical literature demonstrating the involvement of cyclic nucleotide-dependent signaling in neuronal and behavioral responses to alcohol, as well as detailing the capacity of various PDE inhibitors to modulate alcohol intake. Together these data provide a framework for evaluating the potential utility of PDE inhibitors as novel treatments for alcohol use disorders.

show abstract

“…In contrast to the results obtaining with PD1 inhibition, the PDE4 inhibitor rolipram, which acts specifically on the cAMP cascade (Beavo, 1995), failed to restore OD plasticity in the ferret model of FASD even when tested with different doses (0.5 mg/kg, 1.25 mg/kg and 2.5 mg/kg) (Krahe et al, 2010). Because of the distinct results obtained with rolipram (acting specifically on cAMP) and vinpocetine (acting on both cAMP and cGMP) it is possible that the positive effects of PDE1 inhibitors are due to activation of the cGMP cascade.…”

Section: Introductionmentioning

confidence: 87%

Early alcohol exposure disrupts visual cortex plasticity in mice

Lantz

Wang

Medina

2012

Intl J of Devlp Neuroscience

Self Cite

View full text Add to dashboard Cite

There is growing evidence that deficits in neuronal plasticity underlie the cognitive problems seen in fetal alcohol spectrum disorders (FASD). However, the mechanisms behind these deficits are not clear. Here we test the effects of early alcohol exposure on ocular dominance plasticity (ODP) in mice and the reversibility of these effects by phosphodiesterase (PDE) inhibitors. Mouse pups were exposed to 5 g/kg of 25% ethanol i.p. on postnatal days (P) 5, 7 and 9. This type of alcohol exposure mimics binge drinking during the third trimester equivalent of human gestation. To assess ocular dominance plasticity animals were monocularly deprived at P21 for 10 days, and tested using optical imaging of intrinsic signals. During the period of monocular deprivation animals were treated with vinpocetine (20mg/kg; PDE1 inhibitor), rolipram (1.25 mg/Kg; PDE4 inhibitor), vardenafil (3 mg/Kg; PDE5 inhibitor) or vehicle solution. Monocular deprivation resulted in the expected shift in ocular dominance of the binocular zone in saline controls but not in the ethanol group. While vinpocetine successfully restored ODP in the ethanol group, rolipram and vardenafil did not. However, when rolipram and vardenafil were given simultaneously ODP was restored. PDE4 and PDE5 are specific to cAMP and cGMP respectively, while PDE1 acts on both of these nucleotides. Our findings suggest that the combined activation of the cAMP and cGMP cascades may be a good approach to improve neuronal plasticity in FASD models.

show abstract

Phosphodiesterase Type 4 Inhibition Does Not Restore Ocular Dominance Plasticity in a Ferret Model of Fetal Alcohol Spectrum Disorders

Cited by 5 publications

References 49 publications

Overexpression of Serum Response Factor Restores Ocular Dominance Plasticity in a Model of Fetal Alcohol Spectrum Disorders

Overexpression of Serum Response Factor Restores Ocular Dominance Plasticity in a Model of Fetal Alcohol Spectrum Disorders

Phosphodiesterase regulation of alcohol drinking in rodents

Early alcohol exposure disrupts visual cortex plasticity in mice

Contact Info

Product

Resources

About