Bcl-2 overexpression per se does not promote regeneration of neonatal crushed optic fibers.

We have explored whether overexpression of the bcl-2 gene 'per se' can promote regeneration of retinal ganglion cells (RGCs) after optic nerve axotomy in developing transgenic mice. We have used newborn mice (postnatal day 5) because at this age the central nervous system environment is more permissive for regeneration than in adults, thus, maximizing the probability to detect a regeneration-promoting role of bcl-2. Thirty days postsurgery we found that in mice overexpressing bcl-2, a high proportion of retinal ganglion cells survived and also that some fibers in the proximal stump of the optic nerve were preserved. However, the optic nerve of transgenic mice does not show signs of regeneration. On the contrary, in the presence of Schwann cell transplants, there are signs of fiber regrowth. Indeed, many axonal terminals cross the crush site and reach the chiasm in both wild type and transgenic mice nerves. These results suggest that bcl-2 overexpression is not sufficient 'per se' to increase the regenerative potentiality of axotomized RGCs.

Effects of neurotrophins on cortical plasticity: same or different?

Neurotrophins are important regulators of visual cortical plasticity. It is still unclear, however, whether they play similar or different roles and which are their effects on the electrical activity of cortical neurons in vivo. We therefore compared the effects of all neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-3) on visual cortical plasticity and on cell spontaneous and visually evoked activity. Rats were monocularly deprived for 1 week at the peak of the critical period, and neurotrophins were infused intracortically. The main finding is that, with the exception of NT-3, all neurotrophins affect the outcome of monocular deprivation, but there are clear differences in their mechanisms of action. In particular, NT-4 and NGF counteract monocular deprivation effects without causing detectable alterations either in spontaneous or visually evoked neuronal activity. BDNF is less effective on ocular dominance plasticity and, in addition, strongly affects spontaneous and visually evoked activity in cortical neurons.

Effects of nerve growth factor on visual cortical plasticity require afferent electrical activity.

It is known that administration of nerve growth factor (NGF) prevents the ocular dominance shift induced by monocular deprivation in the rat. To determine whether electrical activity in the visual afferent pathway is required for NGF effects on ocular dominance, we infused NGF into the cortex of animals subjected to complete monocular blockade of retinal discharges. Rats at the peak of the critical period received intravitreal tetrodotoxin (TTX) injections to silence activity in one eye for a period of 6-7 days; NGF was concurrently delivered into the visual cortex by means of osmotic minipumps. At the end of the treatment period, the ocular dominance distribution of cortical neurons was assessed by single-cell recordings. The results demonstrate that while infusion of NGF is effective in preventing the ocular dominance shift in lid-sutured rats, virtually no rescue can be observed in TTX-injected animals. Identical results were obtained when a specific agonist of the NGF receptor TrkA, the bivalent anti-rat TrkA IgG (RTA), was infused into the cortex in place of NGF. We conclude that NGF signalling via the TrkA receptor must be coupled to afferent electrical activity to produce its effects on the eye preference of cortical neurons. This suggests a generalized mechanism in which high-affinity neurotrophin receptor activation and afferent discharge interact to modulate neuronal plasticity in the developing visual cortex.

Expression of the transcription factor Zif268 in the visual cortex of monocularly deprived rats: effects of nerve growth factor.

Neurotrophins are known to be involved in experience-dependent plasticity of the visual cortex. Here, we have characterized in detail the effects of intraventricular nerve growth factor infusion in monocularly deprived rats by using immunostaining for the immediate-early gene product Zif268 as a marker of functional activity with cellular resolution. We have taken advantage of the rapid regulation of Zif268 by visual input to reveal the cortical units that are responsive to the deprived eye after a period of monocular deprivation. We found that responses to the deprived eye were significantly preserved in the cortex of monocularly deprived rats infused with nerve growth factor. The effects of nerve growth factor were greater for cortical cells located in deep layers and with more peripheral receptive fields. Results from Zif268 staining correlated very well with those obtained by single-cell recordings from the visual cortex. Our results demonstrate that exogenous nerve growth factor preserves the functional input from the deprived eye, enabling cortical neurons to activate immediate-early gene expression in response to stimulation of the deprived eye. Furthermore, we show that the intraventricular infusion of nerve growth factor differentially affects the ocular dominance of cells at various depths and eccentricities in the developing cortex.

Role of neurotrophins in neural plasticity: what we learn from the visual cortex.

A role for neurotrophins in regulating cortical developmental plasticity has clearly emerged in these last years. In this review we first present a summary of the early data on the action of NGF in visual cortical development and plasticity in the rat and of the actions of the other neurotrophins in the visual cortex of other mammals. In addition, in order to clarify the differences in the results obtained with the various neurotrophins in different animal preparations we also report new data on the action of NGF, BDNF, NT3 and NT4 in the same preparation, namely the visual cortex of the rat. We discuss old and new results in a physiological model where different neurotrophins play different roles in regulating visual cortical development and plasticity by acting on different neural targets, such as LGN afferents, intracortical circuitry and subcortical afferents and propose a tentative scheme summarizing these actions.