Administration of neurotrophins during dark rearing can replace the lack of visual experience

Without visual experience the visual cortex does not develop normally, and it remains largely immature even after the end of the critical period (Fagiolini et al., 1994; Timney et al., 1978). The classical signs of dark-rearing effects on cortical development are reported in Figure 4.3 and include abnormal habituation of cortical responses and decreased visual acuity.

Following the experiments on the effects of NGF in monocularly deprived animals, the hypothesis was advanced that visual experience during development promotes normal maturation of the visual cortex by regulating the availability of neurotrophins to visual cortical circuits or to structures projecting to them (Fagiolini et al., 1997; Pizzorusso et al., 1997). The physiological alterations induced by lack of visual experience in dark-reared animals could be due simply to an alteration in the level of expression of neurotrophins in the visual cortex. If so, increasing the availability of neurotrophins could replace, at least partly, the lack of visual experience during dark rearing. This hypothesis has been tested for NGF and BDNF.

Supplying animals with suitable doses of neurotrophins during the whole period of dark rearing poses technically difficult problems. It is known that neurotrophins do not cross the blood-brain barrier and therefore must be administered directly to the brain. Daily administration of neurotrophins, for instance, into the ventricles, is practically impossible or troublesome during dark rearing. To overcome this problem, three different methods have been used. All of them have been successful and could have a bearing on clinical applications of neurotrophins in humans. Conceptually the first two methods are very similar, in that they aim at implanting in the lateral ventricles biological minipumps delivering sufficient doses of neurotrophins (in this case NGF) throughout the whole period of dark rearing. As biological minipumps, either Schwann cells or polymer-encapsulated cells genetically engineered to release NGF have been employed (for details of the methods and results, see Fagiolini et al., 1997; Pizzorusso et al., 1997).

The results, summarized in Figure 4.3, show that NGF allows a normal or nearly normal development in dark-reared animals with respect to the tested parameters. In particular, Figure 4.3 shows that development of visual acuity is normal in dark-reared rats treated with NGF.

More recently, the problem of supplying neurotrophins to the CNS has been solved by taking advantage of BDNF overexpression in the postnatal forebrain of mice (Huang et al., 1999; see Fig. 4.7). Also in these animals, all tested parameters were normal despite dark rearing (Fig. 4.3).

In addition, in dark-reared BDNF-overexpressing mice we have observed that the critical period, which is normally prolonged by dark rearing, ends at the same time as in normally reared wild-type mice (P45). Thus, development of visual function can proceed almost normally even in the absence of visual experience, provided that neurotrophins are supplied.

A possible interpretation of these results is that visual experience controls development of visual function by controlling the expression of neurotrophins. Indeed, expression and function of neurotrophins are altered in dark-reared animals (Castren et al., 1992; Pollock et al., 2001; Viegi et al., 2002), suggesting that the effects of dark rearing could, at least in part, be attributed to the lack of appropriate neurotrophin action.

This allows us to speculate that neurotrophins engage in an innate program of visual development which is normally triggered by visual experience. This program is dependent on activity in the visual pathways, in particular on spontaneous activity. Blockage of spontaneous activity of retinal ganglion cells, at least in the case of monocular deprivation, caused a failure of NGF action (Caleo et al., 1999).

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