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Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection ´ A. Hennigan, R.M. O’Callaghan and A.M. Kelly1 Department of Physiology, School of Medicine, and Trinity College Institute of Neuroscience, University of Dublin, Trinity College, Dublin 2, Ireland

Abstract It is beyond doubt that the neurotrophin family of proteins plays key roles in determining the fate of the neuron, not only during embryonic development, but also in the adult brain. Neurotrophins such as NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) can play dual roles: first, in neuronal survival and death, and, secondly, in activity-dependent plasticity. The neurotrophins manifest their effects by binding to two discrete receptor subtypes: the Trk (tropomyosin receptor kinase) family of RTKs (receptor tyrosine kinases) and the p75NTR (p75 neurotrophin receptor). The differential activation of these receptors by the mature neurotrophins and their precursors, the proneurotrophins, renders analysis of the biological functions of these receptors in the adult brain highly complex. Here, we briefly give a broad review of current knowledge of the roles of neurotrophins in the adult brain, including expression of hippocampal plasticity, neurodegeneration and exercise-induced neuroprotection.

Neurotrophins and their receptors The seminal work of a group of embryologists in the early 1950s led to the discovery and description of the family of proteins termed neurotrophins. The most extensively researched neurotrophins to date remain NGF (nerve growth factor) [1], the first to be discovered, and BDNF (brain-derived neurotrophic factor) [2]. NT3 (neurotrophin 3) and NT4 complete the group of neurotrophins known to be expressed in the mammalian brain. These proteins play key roles in development of the nervous system, but they are also responsible for important functions in the adult brain, which will be the focus of this minireview. These functions are two-fold: first in trophic support of adult neurons and secondly in expression of the activity-dependent plasticity that is a defining feature of the brain throughout life. The neurotrophins are initially synthesized as proneurotrophin precursors whose enzymatic cleavage yields the mature neurotrophins. The discovery that proneurotrophins are biologically active [3] has revolutionized the field of neurotrophin research, necessitating the re-evaluation of much published data. Biological activity has also been attributed to two other peptides produced as a result of proNGF cleavage, LIP1 and LIP2 [4,5], which have been shown to protect against excitotoxininduced cell death.

Key words: brain-derived neurotrophic factor (BDNF), long-term potentiation (LTP), nerve growth factor (NGF), neurodegeneration, p75 neurotrophin receptor (p75NTR), tropomyosin receptor kinase (Trk). Abbreviations used: AD, Alzheimer’s disease; BDNF, brain-derived neurotrophic factor; LPS, lipopolysaccharide; LTD, long-term depression; LTP, long-term potentiation; NGF, nerve growth factor; NT3, neurotrophin 3; p75NTR, p75 neurotrophin receptor; RTK, receptor tyrosine kinase; Trk, tropomyosin receptor kinase. 1 To whom correspondence should be addressed (email [email protected]).


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The diverse functions of the neurotrophins are effected via two classes of receptor: the Trk (tropomyosin receptor kinase) family of RTKs (receptor tyrosine kinases) and p75NTR (p75 neurotrophin receptor). Upon ligand binding, Trk receptors dimerize and become catalytically active, resulting in receptor autophosphorylation and subsequent activation of a number of signalling cascades, including the Ras/ Raf/MAPK (mitogen-activated protein kinase) [6], PI3K (phosphoinositide 3-kinase) [7], and phospholipase C-γ 1 pathways [8]. Trk receptor subtypes bind mature neurotrophins with different specificities; TrkA preferentially binds NGF, TrkB preferentially binds BDNF and NT4, while TrkC displays preference for NT3. The p75NTR binds all mature neurotrophins with approximately equal low affinity and has, in recent years, been demonstrated to bind the proneurotrophins with high affinity [3]. p75NTR can also interact with a number of receptors, including the Trks [9], sortilin [10], and NOGO [11], and is capable of binding ligands other than the neurotrophins, e.g. the rabies virus [12], β-amyloid [13] and prion peptides [14]. Signalling mediators activated subsequent to p75NTR ligand binding include ceramide [15], NF-κB (nuclear factor κB) [16], Akt (also called protein kinase B) [17], JNK (c-Jun N-terminal kinase) [18] and the cysteine proteases, termed caspases [19]. The complexity of this multiple ligand, multiple receptor signalling system is evidenced by the often-opposing actions of the neurotrophins; for example, Trk receptors are widely reported to promote cell survival and enhancement of the efficacy of synaptic transmission, while strong evidence exists in support of a role for p75 in mediation of cell death and in functional impairment, as will be outlined in subsequent sections.

Neurological Disorders: Molecules, Mechanisms and Therapeutics

Neurotrophins and neuronal fate Neurodegeneration has been a focus of research activity for some time, yet many questions remain regarding the mechanisms that determine whether a neuron lives, dies or suffers a functional impairment. It is beyond doubt that the neurotrophins and their receptors are key players in this phenomenon, not only during development, as has been reviewed elsewhere [20,21], but also in the adult brain. Trk receptors have long been known to mediate trophic support of adult neurons; a number of studies show that decreased expression of these receptors is associated with cell loss. Interestingly, while p75NTR expression is greatly reduced in a variety of cell types in adulthood, its expression can be robustly induced by injury. A number of studies have reported that this injuryinduced expression is closely correlated with the degenerative effects observed following the trauma. Expression of p75NTR is increased in rat motor neurons following sciatic nerve lesion [22] and in the hippocampus following seizure (and in this case is tightly correlated with apoptosis) [23] and is also associated with neuronal degeneration following experimentally induced ischaemia [24]. The binding of βamyloid to the p75NTR has been shown to induce apoptosis and has been suggested as a possible mechanism contributing to the pathology of AD (Alzheimer’s disease) [13]. In addition, increased levels of proNGF have been observed in certain pathological states, including AD [25]. The results of these studies have led researchers to question the function of the re-expression of the p75NTR under certain pathological conditions and whether or not it may be responsible for cell death. In our laboratory, we employ a number of models of neurodegeneration in order to probe the role of the neurotrophins and their receptors in degenerative events in the rat dentate gyrus, namely aging, kainic acid-induced excitotoxic damage, and peripheral administration of the bacterial endotoxin LPS (lipopolysaccharide), each of which has been linked to aberrant expression of neurotrophins and their receptors [26– 29]. We have found that experimentally induced damage in the adult brain stimulated by kainic acid or by LPS results in increased expression of p75NTR in dentate gyrus with simultaneously observed decreases in Trk expression and in´ creases in cell death ([29a], and A. Hennigan and A.M. Kelly, unpublished work). These results are consistent with the hypothesis that increased p75NTR expression concomitant with a decrease in expression of Trk tips the balance away from cell survival in favour of cell death.

Neurotrophins and hippocampal plasticity A large body of literature supports the hypothesis that both NGF and BDNF play fundamental roles in synaptic plasticity in the hippocampus, a region of the archicortex vital for expression of learning and memory. Experimental investigation of the functions of the hippocampus have focused to a large degree on expression of LTP (long-term potentiation), a cellular analogue of learning and memory [30], and spatial

learning tasks such as navigation of the water maze [31]. We have demonstrated a specific role for NGF/TrkA in expression of LTP in the rat dentate gyrus [32–34], while other groups have demonstrated LTP-associated roles not only for NGF and its receptor, but also for BDNF and TrkB (e.g. [35– 37]). Indeed, the literature on the role of BDNF in LTP has outstripped that of NGF, and a form of plasticity induced by BDNF has been well described by Bramham and Messaoudi [38]. A wealth of data also illustrates a role for NGF and BDNF, signalling via Trk receptors, in a variety of forms of hippocampal-dependent learning (e.g. [39,40]). While the role of Trk receptors in modulation of hippocampal plasticity has been extensively investigated, it is only in recent years that such a function has been ascribed to p75NTR, albeit a contrasting one. Greferath et al. [41] reported that p75NTR-knockout mice display improved spatial learning when compared with their wild-type counterparts, suggesting a negative regulation of plasticity by the receptor. With regard to electrophysiological investigations, it has recently been shown that mice lacking p75NTR display intact LTP, but an impairment in LTD (long-term depression) that is associated with an alteration in expression of AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subunits [42]. Another key study demonstrated a facilitation of LTD by proBDNF, which was linked to altered expression of subunits of another ionotropic glutamate receptor, the NMDA (N-methyl-D-aspartate) receptor [43]. Using our models of neurodegeneration described above, we have generated data showing that up-regulation of p75NTR is associated with impairments in LTP and in spatial learning, again indicating a negative regulation of plasticity by p75NTR ´ ([29a], and A. Hennigan and A.M. Kelly, unpublished work). Thus it is clear that the duality of function of the neurotrophin family of proteins in the context of cell survival and death also extends to the expression of plasticity in the adult brain.

Neurotrophins and neuroprotection While, as outlined above, neurotrophins have taken their place at the centre of investigations of the regulation of certain mechanisms of cell death, at the other end of the spectrum they appear to be crucial mediators of positive effects within the brain, such as cognitive enhancement and neuroprotection. A large number of studies have highlighted physical activity as a key intervention in promoting these effects, with BDNF expression now firmly established as a causal factor [44], although exercise-induced increases in NGF expression have also been reported. The positive effects of exercise on many physiological systems, including the CNS (central nervous system), are well established. Exercise-induced improvements in learning and memory have been directly associated with improved neurogenesis, an increase in activitydependent synaptic plasticity and altered gene expression [45,46], with many of these improvements observed in the hippocampus. The consistent exercise-induced up-regulation of BDNF expression may, by enhancing trophic support in key brain areas, provide a simple tool for ameliorating
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the decline in brain function that results from various forms of neurodegeneration. Indeed, numerous studies have highlighted the ability of exercise to protect against a variety of models of experimentally induced neuronal damage via a BDNF-linked mechanism. A variety of exercise regimes appear to have the capability to induce positive effects on neuronal function, with forced treadmill running, forced swimming and voluntary wheel running each being reported to confer neuroprotection. It has been widely reported that aged animals or those exposed to experimental brain insult demonstrate spatial learning deficits that can be ameliorated by prior exercise, e.g. spatial learning is enhanced in aged rats engaging in mild forced treadmill exercise [47], while forced swimming has been reported to prevent the agerelated decline in performance of the passive avoidance task in middle-aged animals [48]. In support of these findings, we have recently observed enhancements in LTP and hippocampal-dependent learning in young rats following 1 week of exercise training; the same training protocol reversed agerelated deficits in middle- aged and aged rats ([48a], and ´ R.M. O’Callaghan and A.M. Kelly, upublished work). The potential for exercise to ameliorate these deficits suggests a protective effect of exercise against the degenerative effects of age that fits well with epidemiological data linking physical fitness in old age with decreased incidence of AD and other forms of dementia [49]. In the context of other models of neurodegeneration, kainic acid-induced impairments in water-maze performance in young rats have been shown to be reduced by prior exercise [50], while voluntary exercise rescued deficits in both spatial learning and LTP induced by prenatal ethanol exposure [51]. These profound effects of exercise on neuronal survival and plasticity demonstrate an exciting potential non-pharmacological intervention reliant in part on the neuroprotective abilities we now know BDNF to possess.

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Concluding remarks In the five decades since the first neurotrophin was discovered, roles for these proteins and their receptors have been identified in almost every key area of current neuroscience research. Our understanding of the mechanisms underlying the multiplicity of biological functions in which the neurotrophins partake is advancing rapidly, providing key insights into the cellular mechanisms of neuronal function in health and disease.

We thank the Health Research Board, Ireland, IRCSET (Irish Research Council for Science, Engineering and Technology), Science Foundation Ireland and Higher Education Authority [PRTLI (Programme for Research in Third-Level Institutions)].

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Received 8 September 2006


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