ReviewThe role of the locus coeruleus in the development of Parkinson's disease
Introduction
Following the method of Falck et al. [1], catecholamine-containing neurons in the rat central nervous system (CNS) have been classified into 12 cell groups (A1–A12). Following a regional subdivision, two main norepinephrine (NE) systems can be distinguished: one is composed of neurons belonging to the medulla oblongata, whereas the other is more rostral, and is located in the pons [2]. The caudal NE system is represented by scattered cell groups in the lower brainstem, mainly located in the medullary ventrolateral reticular formation (A1), the dorsal vagal complex, and the nucleus of the solitary tract (A2).
The Locus Coeruleus (LC, A6) represents the most rostral NE complex, being located in the pons, in the upper part of the floor of the fourth ventricle. This rostral NE complex was previously known as Nucleus Pigmentosus Pontis, and is present in all the mammalian species, representing the major source of NE for the CNS [3], [4]. The LC is indeed a nuclear complex, being composed of three distinct nuclear formations located in the pons: the LC sensu stricto,the nucleus subcoeruleus, and scattered catecholamine neurons located in the parabrachial nucleus, respectively [3]. All neurons belonging to this cranial NE system profusely branch their axons to the entire brain. In particular, LC efferents form two main ascending fiber systems: the dorsal bundle, and the much smaller rostral limb of the dorsal periventricular pathway, whereas other LC efferents are distributed caudally to the cerebellum, the lower medulla, and the spinal cord [5]. The activity of cells belonging to the LC complex (from now on simply LC, unless specified as LC sensu stricto) modulates a variety of central functions through the release of NE into several brain areas (for a review, see Ref. [6]). The general physiology of the LC has been extensively investigated in several review papers [7], [8], therefore, here we will just briefly mention the main functions affected by LC activity. For instance, LC plays a central role in the sleep-waking cycle [9] anticipating the fluctuations of electroencephalographic activity [10] and promoting a state of vigilance [11]; in monitoring environmental stimuli [12], [13], [14] with special emphasis on alerting and orienting to novelty [15] as well as in the control of autonomic functions [16]. It is indeed well known that the stimulation of central NE receptors leads to changes in the state of vigilance as well as in immediate early gene (IEG) transcription regulating the expression of c-fos and nerve growth factor-induced A (NGFI A), nur 77, tis-7, zif-268 and tis-21 [17], [18] both in basal conditions [18] and during stress [19]. In line with the increased activity of the nucleus in the waking state, it has been shown that LC activity plays a pivotal role in regulating the circadian rhythm of expression of a group of IEGs and the state of phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) proteins, suggesting that this neuronal complex is critical for inducing cerebral plasticity related to the waking state [20] and, possibly, it could play a role in neuronal repair. In contrast, during REM sleep, when the activity of the nucleus is suppressed, there is a marked reduction in the expression of these genes. Similarly, the lesion of LC nucleus abolishes the waking-related early genes expression [20], and pharmacological agents hyperpolarizing NE neurons like clonidine [21], decrease the expression of these genes below baseline values [22].
As mentioned above, the LC nucleus appears to be constantly affected in PD, as witnessed by the extensive cell loss occurring in PD patients [23]. In contrast, although controversial findings exist, the caudal NE nuclei (A1 and A2) seem to be only slightly affected in PD.
The loss of LC cells in PD has been well documented by various neuropathological studies performed all through the century [24], [25], [26], [27], [28], [29]; however, despite extensive anatomical investigations, only a minority of functional studies have focused on this alteration as a key element of PD.
It should be noted that even in their original paper describing the DA deficiency, Ehringer and Hornykiewicz [30] reported a concomitant marked NE depletion in PD patients (Table 1).
Starting from the first work of Mavridis et al. [31], basic research provided a new provocative hypothesis about the potential significance of LC in conditioning the natural history of PD. In particular, experimental studies carried out during this decade using animal models have investigated the role of NE depletion in the pathogenesis and the natural course of nigrostriatal DA damage. Data are accumulating to support the belief that the central NE system might influence both the onset and the progression of damage to the DA nigrostriatal tract. In particular, it has been demonstrated that a lesion of LC NE neurons has a deleterious effect on the sensitivity of nigrostriatal DA cells to various neurotoxic insults [31], [32], [33], whereas an inborn NE hyperinnervation leads to protection against neurotoxicity to nigrostriatal DA neurons [34]. These data converge to indicate that the loss of NE might play a double role in PD: (1) by itself, partly sustaining PD symptoms; and (2) via a worsening of the DA nigrostriatal damage.
In keeping with this, an increase in NE activity should be considered as a potential protective mechanism that could be elicited in PD patients. Indeed, as mentioned above, animals carrying an inborn NE hyperinnervation of target areas have recently been shown to be resistant to experimental parkinsonism [34]. Similarly, pharmacological stimulation of NE neurons protects from methamphetamine-induced DA neurotoxicity [35].
A critical analysis of this experimental evidence which accumulated in the last decade, is the major aim of the review; whereas anatomical and neurochemical data regularly showing impairment of the central NE system in idiopathic PD will be reviewed briefly, seeing that other reviews have covered the topic extensively [23], [36], [37] respectively.
Section snippets
Anatomical evidence for the involvement of NE neurons in PD
A detailed anatomical analysis of the nucleus and its connections is a preliminary step which appears to be necessary to clarify the significance of degeneration within the LC in relation to PD.
In humans, the LC has a rostrocaudal extension of approximately 16 mm [3], [38] since it begins slightly rostral to the main trigeminal nucleus and extends rostrally as far as the level of the mesencephalic trigeminal nucleus. The nucleus is “tube-like” in shape, and it consists of two kinds of neurons;
Neurochemical evidence concerning the involvement of NE neurons in PD
The biochemical basis of PD was originally defined by the loss of DA in the nigrostriatal pathway [30], [72] and it has been stated that the massive DA deficiency which regularly occurs in the caudate-putamen of PD patients is sufficient to produce the classic symptoms of PD as a movement disorder [37]. This massive DA loss should therefore be regarded as a necessary feature of PD [73]. Nonetheless, as described above, it has been known for many years that in PD neurotransmitters other than DA
Evidence for the involvement of NE in experimental parkinsonism
The above-reviewed role of LC neuron lesions as a constant element of PD should also appear clear from an experimental point of view in a different approach to the disease itself. It is currently accepted that experimental models of PD should solely reproduce the damage to the nigrostriatal DA pathway. This has been achieved either by microinfusing selectively into the SNpc and the medial forebrain bundle the neurotoxin 6-hydroxydopamine (6-OHDA) [79], [80], or by administering systemically
Conclusions
The loss of central NE cells belonging to the LC in PD has been well documented by various neuropathological studies performed during the last few decades. Despite extensive anatomical investigations showing a massive loss of LC cells, only a few studies have focused on this alteration as a key element of the disorder.
Indeed, after the discovery of DA depletion as the causal agent of PD, the vast majority of research studies on the disorder have focused on the nigro-striatal DA pathway and the
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