Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Abstract

Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine ␤-hydroxylase knockout (Dbh؊/؊) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh؊/؊ mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh؊/؊ mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh؊/؊ mice. Finally, striatal levels of phospho-ERK-1/2 and ⌬FosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh؊/؊ mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD.dopamine ͉ Parkinson's disease ͉ dyskinesias ͉ dopamine ␤-hydroxylase P arkinson's disease (PD) affects Ϸ1% of the world's aging population (1). Despite this high prevalence and intensive research into its origins, the etiology of PD remains largely unknown. The disease is characterized by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SN), and symptoms, which tend to manifest when Ϸ80% of striatal DA is lost, include bradykinesia, postural instability, rigidity, and resting tremor. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin, is known to produce parkinsonism in humans and causes severe DA loss in animals (2). Because of its ability to recapitulate the neuropathology of PD, MPTP is used widely in PD research. However, MPTP has been unable to reliably reproduce the motor symptoms of PD in mice, which limits the utility of MPTP-treated mice as an animal model of the disease (3). Differences in mouse strain and experimental paradigms may at least partially account for these inconsistencies.Despite the focus on DA, PD is more accurately described as a multisystem disorder that features a profound albeit underappreciated loss of locus coeruleus (LC) neurons, as well as variable damage to other brain regions (4-6). Postmortem studies indicate that neuronal degeneration in the LC is comparable to that in the substantia nigra pars compacta, and that it may a...

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

“…and increased motor deficits (Archer and Fredriksson, 2006;Bing et al, 1994;Fornai et al, 1997;Mavridis et al, 1991). In our study, increased motor impairments did not seem to be caused by increased DA neuron cell loss, which is in agreement with some studies (Delaville et al, 2012;Pifl et al, 2013;Rommelfanger et al, 2007). Other studies have reported increased DA neurodegeneration, or increased loss of striatal DA, in double lesioned animals (Archer and Fredriksson, 2006;Bing et al, 1994;Fornai et al, 1997;Mavridis et al, 1991;Schmidt, 2003, 2004).…”

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

“…This raises the question of the mechanisms underlying these early motor deficits. In wildtype mice, lesions of the locus coeruleus, which contains the cell bodies of noradrenergic neurons that project throughout the brain, lead to deficits on the challenging beam [70] that are very similar to those we have observed in the Thy1-aSyn mice, suggesting that early deficits in noradrenaline could, if present, contribute to the observed deficits. In addition, young Thy1-aSyn mice exhibit profound alterations at the corticostriatal synapse (and perhaps other synaptic connections) that are described as follows.…”

Assessment of Sensorimotor Function in Mouse Models of Parkinson's Disease

“…The challenging beam test is not only useful at detecting motor performance and coordination deficits in genetic mouse models of PD but is also useful in uncovering impairments in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated and 6-hydroxydopamine-treated mice and norepinephrine deficient mice 19,[23][24][25] . In addition, we find the challenging beam to be less influenced by body weight compared to other tests of motor performance and coordination (rotarod and pole test).…”