Restoration of neuronal plasticity by a phosphodiesterase type 1 inhibitor in a model of fetal alcohol exposure.

Although some studies showed the efficacy of phosphodiesterase (PDE) inhibitors as neuronal plasticity enhancers, little is known about the effectiveness of these drugs to improve plasticity in cases of mental retardation. Fetal alcohol syndrome (FAS) is the leading cause of mental retardation in the western world. Using a combination of electrophysiological and optical imaging techniques, we show here that vinpocetine, a PDE type I inhibitor, restores ocular dominance plasticity in the ferret model of fetal alcohol exposure. Our finding should contribute to a better understanding and treatment of cognitive deficits associated with mental disorders, such as FAS.

Protein synthesis-independent plasticity mediates rapid and precise recovery of deprived eye responses.

Monocular deprivation (MD) for a few days during a critical period of development leads to loss of cortical responses to stimulation of the deprived eye. Despite the profound effects of MD on cortical function, optical imaging of intrinsic signals and single-unit recordings revealed that deprived eye responses and orientation selectivity recovered a few hours after restoration of normal binocular vision. Moreover, recovery of deprived eye responses was not dependent upon mRNA translation, but required cortical activity. Interestingly, this fast recovery and protein synthesis independence was restricted to the hemisphere contralateral to the previously deprived eye. Collectively, these results implicate a relatively simple mechanistic process in the reactivation of a latent set of connections following restoration of binocular vision and provide new insight into how recovery of cortical function can rapidly occur in response to changes in sensory experience.

Early alcohol exposure impairs ocular dominance plasticity throughout the critical period.

Animal models of fetal alcohol syndrome (FAS) have revealed an impairment of sensory neocortex plasticity. Here, we examine whether early alcohol exposure leads to a permanent impairment of ocular dominance plasticity (OD) or to an alteration in the timing of the critical period. Ferrets were exposed to alcohol during a brief period of development prior to eye opening and effects of monocular deprivation examined during early, mid and late critical period. Single-unit electrophysiology revealed markedly reduced OD plasticity at every age examined. This finding provides evidence that early alcohol exposure does not affect the timing or duration of the critical period of OD plasticity and suggests an enduring impairment of neural plasticity in FAS.

Early alcohol exposure induces persistent alteration of cortical columnar organization and reduced orientation selectivity in the visual cortex.

Fetal alcohol syndrome (FAS) is a major cause of learning and sensory deficits in children. The visual system in particular is markedly affected, with an elevated prevalence of poor visual perceptual skills. Developmental problems involving the neocortex are likely to make a major contribution to some of these abnormalities. Neuronal selectivity to stimulus orientation, a functional property thought to be crucial for normal vision, may be especially vulnerable to alcohol exposure because it starts developing even before eye opening. To address this issue, we examined the effects of early alcohol exposure on development of cortical neuron orientation selectivity and organization of cortical orientation columns. Ferrets were exposed to ethanol starting at postnatal day (P) 10, when the functional properties and connectivity of neocortical neurons start to develop. Alcohol exposure ended at P30, just before eye opening at P32. Following a prolonged alcohol-free period (15-35 days), long-term effects of early alcohol exposure on cortical orientation selectivity were examined at P48-P65, when orientation selectivity in normal ferret cortex has reached a mature state. Optical imaging of intrinsic signals revealed decreased contrast of orientation maps in alcohol- but not saline-treated animals. Moreover, single-unit recordings revealed that early alcohol treatment weakened neuronal orientation selectivity while preserving robust visual responses. These findings indicate that alcohol exposure during a brief period of development disrupts cortical processing of sensory information at a later age and suggest a neurobiological substrate for some types of sensory deficits in FAS.

Recovery of cortical binocularity and orientation selectivity after the critical period for ocular dominance plasticity.

Cortical binocularity is abolished by monocular deprivation (MD) during a critical period of development lasting from approximately postnatal day (P) 35 to P70 in ferrets. Although this is one of the best-characterized models of neural plasticity and amblyopia, very few studies have examined the requirements for recovery of cortical binocularity and orientation selectivity of deprived eye responses. Recent studies indicating that different mechanisms regulate loss and recovery of binocularity raise the possibility that different sensitive periods characterize loss and recovery of deprived eye responses. In this report, we have examined whether the potential for recovery of binocularity and orientation selectivity is restricted to the critical period. Quantitative single unit recordings revealed recovery of cortical binocularity and full recovery of orientation selectivity of deprived eye responses following prolonged periods of MD (i.e., >3 wk) starting at P49, near the peak of plasticity. Surprisingly, recovery was present when binocular vision was restored after the end of the critical period for ocular dominance plasticity, as late as P83. In contrast, ferrets that had never received visual experience through the deprived eye failed to recover binocularity even though normal binocular vision was restored at P50, halfway through the critical period. Collectively, these results indicate that there is potential for recovery of cortical binocularity and deprived eye orientation selectivity after the end of the critical period for ocular dominance plasticity.

Neonatal alcohol exposure induces long-lasting impairment of visual cortical plasticity in ferrets.

Fetal alcohol syndrome is a major cause of learning and sensory deficits. These disabilities may result from disruption of neocortex development and plasticity. Alcohol exposure during the third trimester equivalent of human gestation may have especially severe and long-lasting consequences on learning and sensory processing, because this is when the functional properties and connectivity of neocortical neurons start to develop. To address this issue, we used the monocular deprivation model of neural plasticity, which shares many common mechanisms with learning. Ferrets were exposed to ethanol (3.5 mg/kg, i.p.) on alternate days for 3 weeks starting on postnatal day (P) 10. Animals were then monocularly deprived at the peak of ocular dominance plasticity after a prolonged alcohol-free period (15-20 d). Quantitative single-unit electrophysiology revealed that alcohol exposure disrupted ocular dominance plasticity while preserving robust visual responses. Moreover, optical imaging of intrinsic signals revealed that the reduction in visual cortex area driven by the deprived eye was much less pronounced in ethanol-treated than in control animals. Alcohol exposure starting at a later age (P20) did not disrupt ocular dominance plasticity, indicating that timing of exposure is crucial for the effects on visual plasticity. In conclusion, alcohol exposure during a brief period of development impairs ocular dominance plasticity at a later age. This model provides a novel approach to investigate the consequences of fetal alcohol exposure and should contribute to elucidate how alcohol disrupts neural plasticity.

Different mechanisms for loss and recovery of binocularity in the visual cortex.

Diverse molecular mechanisms have been discovered that mediate the loss of responses to the deprived eye during monocular deprivation. cAMP/Ca2+ response element-binding protein (CREB) function, in particular, is thought to be essential for ocular dominance plasticity during monocular deprivation. In contrast, we have very little information concerning the molecular mechanisms of recovery from the effects of monocular deprivation, even though this information is highly relevant for understanding cortical plasticity. To test the involvement of CREB activation in recovery of responses to the deprived eye, we used herpes simplex virus (HSV) to express in the primary visual cortex a dominant-negative form of CREB (HSV-mCREB) containing a single point mutation that prevents its activation. This mutant was used to suppress CREB function intracortically during the period when normal vision was restored in two protocols for recovery from monocular deprivation: reverse deprivation and binocular vision. In the reverse deprivation model, inhibition of CREB function prevented loss of responses to the newly deprived eye but did not prevent simultaneous recovery of responses to the previously deprived eye. Full recovery of cortical binocularity after restoration of binocular vision was similarly unaffected by HSV-mCREB treatment. The HSV-mCREB injections produced strong suppression of CREB function in the visual cortex, as ascertained by both DNA binding assays and immunoblot analysis showing a decrease in the expression of the transcription factor C/EBPbeta, which is regulated by CREB. These results show a mechanistic dichotomy between loss and recovery of neural function in visual cortex; CREB function is essential for loss but not for recovery of deprived eye responses.

cAMP/Ca2+ response element-binding protein function is essential for ocular dominance plasticity.

The monocular deprivation model of amblyopia is characterized by a reduction in cortical responses to stimulation of the deprived eye. Although the effects of monocular deprivation on the primary visual cortex have been well characterized physiologically and anatomically, the molecular mechanisms underlying ocular dominance plasticity remain unknown. Previous studies have indicated that the transcription factor adenosine cAMP/Ca(2+) response element-binding protein (CREB) is activated during monocular deprivation. However, it remains unknown whether CREB function is required for the loss of cortical responses to the deprived eye. To address this issue, we used the herpes simplex virus (HSV) to express a dominant negative form of CREB (HSV-mCREB) containing a single point mutation that prevents its activation. Quantitative single-unit electrophysiology showed that cortical expression of this mutated form of CREB during monocular deprivation prevented the loss of responses to the deprived eye. This effect was specific and not related to viral toxicity, because overexpression of functional CREB or expression of beta-galactosidase using HSV injections did not prevent the ocular dominance shift during monocular deprivation. Additional evidence for specificity was provided by the finding that blockade of ocular dominance plasticity was reversible; animals treated with HSV-mCREB recovered ocular dominance plasticity when mCREB expression declined. Moreover, this effect did not result from a suppression of sensory responses caused by the viral infection because neurons in infected cortex responded normally to visual stimulation. These findings demonstrate that CREB function is essential for ocular dominance plasticity.