Nd

20% Proprioceptive neurons missing

60% Proprioceptive and cutaneous mechanoreceptors missing

Neuronal losses are expressed as the percentage of neurons lost in mutant compared to wild-type controls. n.s. = not significantly different. ND = not determined. Only some of the populations examined in the original papers are reported for the sake of brevity.

specific neuronal populations in the peripheral and autonomic nervous systems fail to develop or do not survive (see Box 1). For instance, in mice deficient in trkA or NGF, virtually all sympathetic neurons in the superior cervical ganglion die, while in mice deficient in trkC or NT3, proprioceptive neurons die.

At variance with what is found in the peripheral or auto-nomic nervous system, no central nervous system (CNS) population is solely dependent on one neurotrophin for its survival. Indeed, in neurotrophin knockout mice, there is no loss of any specific population of neurons in the CNS (Thoenen, 1995).1

With hindsight, this observation already hinted at the possibility that the role of neurotrophins in the CNS was not neuronal survival. However, it took a completely dif ferent series of experiments to show clearly that neu-rotrophins have an important role in the plasticity of the CNS, leading to the formulation of a new neurotrophic hypothesis. These experiments were performed in the developing visual system.

1 Note: Several authors have employed neurotrophins to save neurons from lesion-induced death. Paradigmatic is the effect of NGF on the survival of cholinergic basal forebrain neurons after axotomy. Retinal ganglion cell survival is also increased by exogenous neurotrophins. This, however, does not mean that the exogenous neurotrophin can substitute for the loss of the target-derived endogenous one. Indeed, blockage of axonal transport does not cause appreciable death of retinal ganglion cells.

Functional properties of mammalian visual cortical neurons are immature at eye opening and develop gradually during the first months of postnatal life (Fagiolini et al., 1994). Development of the visual system is strongly influenced by depriving one eye of patterned vision during a short period of postnatal development called the critical period for the effects of monocular deprivation (which, from now on, will be referred to as simply the critical period). Modifications of cortical circuitry in response to an imbalance between the inputs from the two eyes are extremely rapid; for instance, a few hours of monocular deprivation during the critical period are sufficient to shift the ocular dominance distribution of visual cortical cells toward the nondeprived eye, and a few days are enough to produce a shift which is equal to that induced by a deprivation lasting for the entire critical period. What are the mechanisms leading to such dramatic modifications of cortical connections?

Wiesel and Hubel introduced in visual physiology the important concept of binocular competition (Wiesel and Hubel, 1963). The two eyes compete for functional possession of the binocular cortical neurons, and the competition takes the form of electrical activity. If electrical activity in the two sets of thalamic fibers, those driven by the contralateral eye and those driven by the ipsilateral eye, is temporally correlated, then both sets of fibers will be allowed to maintain connections with the same cortical neuron. If, however, the activity in the two sets of fibers is not temporally correlated, only one set of fibers will be allowed to keep its hold on the post-synaptic neuron, the one whose activity is more able to drive it. In normal development, where the activity in the two sets of fibers driven by either eye is equally strong and temporally patterned, this process of activity-dependent competition leads to the existence of binocular neurons and to a balanced ocular dominance distribution: neurons in the visual cortex have very similar probabilities of being dominated by either eye. During monocular deprivation the competition between the two eyes becomes uneven, because electrical activity in the afferent fibers driven by the deprived eye is both uncorrelated with that of the fibers driven by the undeprived eye and weaker; as a result, the closed eye loses the fight at cortical level, leaving the dominance of cortical neurons to the undeprived eye.

It is not clear what the two eyes compete for at a molecular level. A reasonable hypothesis is that they compete for a reward important for their function. A reward can be thought of as chemical messages that strengthen nervous connections; therefore, it can be said that the two eyes, during development, compete for eating. Our initial hypothesis (see Fig. 4.1B) was that the fibers driven by either eye compete for a neurotrophic factor available in only a limited amount at cortical level (Maffei et al., 1992).

This introduced the neurotrophic hypothesis in the CNS, transforming neurotrophins from survival factors for neurons, derived from nonneuronal targets, to survival factors for neural connections, exchanged from neuron to neuron as they establish functional connections. This new neurotrophic hypothesis envisaged two broad fields of action for neurotrophins in the CNS. The first stage could influence the probability of formation of synaptic contacts between incoming fibers and target neurons. The second stage could be the regulation of synaptic efficacy, maintenance of connections, and development of a function, as in binocular vision development. This hypothesis implies that the production and uptake of the neurotrophic factor are functions of the quantity and pattern of electrical activity at both presynaptic and postsynaptic levels, and that neu-rotrophic factors, in turn, can enhance synaptic transmission at both the functional and morphological levels, thus firmly linking together neurotrophins and electrical activity in the control of visual development. It should be noted that at the time this new hypothesis concerning the role of neu-rotrophins in activity-dependent synaptic plasticity was put forth, the reciprocal control between neurotrophins and electrical activity, now well characterized, was totally unknown. The first demonstrations that neurotrophin production was under the control of electrical activity occurred around 1990 (Ernfors et al., 1991; Zafra et al., 1990), showing that artificially increasing the electrical activity in the hippocampus or neocortex increased both the mRNA and protein of neurotrophins; later on, it was shown that this also promoted their release (Blochl and Thoenen, 1995). Also, protocols inducing long-term potentation (LTP) in the hippocampus were then shown to increase neurotrophin mRNA (Castren et al., 1993). Complementary to this, a decrease of activity by tetradotoxin (TTX) decreased neurotrophin mRNA (Castren et al., 1992).

In addition to the two main differences already pointed out between the classical neurotrophic hypothesis for the PNS and the new one for the CNS (formation and survival of connections and not of neurons, produced by neurons and not by nonneuronal targets), another difference is emerging from the literature, namely, the possibility of an anterograde action of neurotrophins as opposed to the classical target-derived action. This significantly changes the frame of thought: in addition to thinking that cortex-derived factors guide, in concert with electrical activity, stabilization of thalamic afferents on cortical neurons, we may have to consider that thalamic fibers themselves release factors which promote and guide the formation and maintenance of their synapses on cortical neurons and that corticothala-mic afferents may contribute to the development of the pattern of thalamocortical connectivity The evidence for anterograde actions is illustrated in Box 2.

Box 2. Anterograde and Retrograde Actions of Neurotrophins

Following the experiments in the PNS, the concept had been accepted that neurotrophins are transported retrogradely and that this is the basis of their action.

This idea has been passively extended to the interpretation of CNS data.

In some instances, particularly for NGF and the cholinergic projection from the basal forebrain to the hippocampus, this assumption seems to hold. In other cases, it is supported only by the observation that exogenous neu-rotrophins injected into specific brain regions are retrogradely transported. However, recent experiments studying the transport of BDNF/NGF in the optic nerve of the rat have shown that the situation is somewhat more complicated. If one ligates the optic nerve and observes the accumulation of neurotrophins at both sides of the ligature, only accumulation of BDNF on the retinal side is seen; by contrast, if NGF and BDNF are injected in the superior colliculus and lateral geniculate nucleus, both promptly accumulate at the distal side of the ligature. This suggests that transport of exogenous neurotrophins is not proof of the transport of endogenous ones and that anterograde actions are more important than was previously thought (Caleo et al., 2000). Evidence for anterograde actions has also been obtained in the visual cortex (Kohara et al., 2001) and in the chick visual system (von Bartheld et al., 1996).

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