Subthalamic nucleus‐mediated excitotoxicity in parkinson's disease: A target for neuroprotection

Abstract

Dopamine deficiency causes disinhibition and overactivity of the subthalamic nucleus (STN). Output neurons from the STN are excitatory and use glutamate as a neurotransmitter. They project to the external and internal segments of the globus pallidum (GPe and GPi), die substantia nigra pars reticulata (SNr), and the pedunculopontine nucleus (PPN). In addition, STN neurons provide excitatory innervation to dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) that contain glutamate receptors. Stimulation of the STN induces bursting activity in SNc dopaminergic neurons. This raises the possibility that the disinhibition of STN neurons that occurs as a result of a dopamine lesion might induce excitotoxic damage in target structures, including the SNc. In addition, the reduction in complex I activity found in the nigra in Parkinson's disease (PD) may cause mitochondrial dysfunction and make SNc dopaminergic neurons vulnerable to even physiologic concentrations of glutamate. We postulate that the dopamine loss that occurs in PD produces augmented STN activity which, in turn, causes further damage to vulnerable dopaminergic neurons, thereby creating a scenario for an increasing cycle of neuronal loss in the SNc. In addition, STN overactivity could, in theory, cause damage to the GPi, SNr, and PPN and thereby account for the development of parkinsonian features that do not respond to levodopa in patients with advanced disease. This hypothesis suggests that pharmacologic or surgical therapies that reduce STN neuronal overactivity or block glutamate receptors in the SNc and other target structures might be neuroprotective and might slow or halt the progression of neurodegeneration in PD.Rodriguez MC, Obeso JA, Olanaw CW. Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for neuroprotection. Ann Neurol 1998;44(Suppl 1):S175-S188The subthalamic nucleus (STN) is a key structure in the functional organization of the basal ganglia. 1 ' 2 For merly considered to have inhibitory projections, its neurons are now known to be excitatory and to use glutamate as a neurotransmitter. 3 In primates, the STN projects to both the globus pallidus pars interna (GPi) and the substantia nigra pars reticulata (SNr), as well as to the globus pallidus pars externa (GPe), the substan tia nigra pars compacta (SNc), the putamen, and the pedunculopontine tegmental nucleus (PPN) in the brainstem.' A (Fig 1). The STN receives inhibitory GABAergic projections from the GPe 2 and excitatory glutamatergic afferents from the sensorimotor cortex, 5 the parafascicular nucleus of the thalamus, and the PPN. 7 The PPN also sends GABAergic and cholinergic efferents to the STN. 7 In addition, dopaminergic affer ents to the STN have been described in monkeys. 8 Anatomic and physiologic data conclusively indicate that output neurons of the STN in the rat and monkey are excitatory and use glutamate as their transmitter.Inactivation of STN induces a reduction in metabolic activity, mitochondrial enzyme activity, glutamic acid...

Central Serotonin2C Receptor: From Physiology to Pathology

“…This treatment, however, is characterized by a declining efficacy and the occurrence of disabling side-effects [200]. Functional inhibition of GPi or STN has provided an alternative to lesioning, by deep brain stimulation associated with modest side-effects [201]. As already mentioned, 5-HT 2C receptors are located in the SNr and medial segment of the pallidal complex in the rat and human brain [121,131], and enhanced 5-HT 2C receptormediated transmission within the output regions of the basal ganglia in parkinsonism appears to contribute to their overactivity [202].…”

Unilateral subthalamic nucleus lesioning: a safe and effective treatment for Parkinson's disease

“…Such knowledge made possible the comprehension of the genesis of the cardinal manifestations of PD 1,[3][4][5][6][7] and how to better treat them surgically 1 . Besides, a new hypothesis has been advanced: the excitotoxic effect of STN glutamate on dopaminergic cells of substantia nigra pars compacta (SNC) would act as a perpetuating mechanism of dopaminergic cell death and PD progression 3,4,7,11 .…”

Combining functional imaging with brain stimulation in Parkinson's disease

“…However, functional imaging using [ 11 C] raclopride, a D2 dopamine receptor antagonist ligand, failed to show any change in striatal dopamine release (Strafella et al, 2003;Thobois et al, 2003), but this may be due to the relatively poor sensitivity of raclopride for detecting low levels of DA release (Ballanger et al, 2009a). That said, numerous preclinical studies have shown that silencing of the STN via lesion or DBS may exert neuromodulative effects on nigral dopamine neurons (Piallat et al, 1996;Rodriguez et al, 1998). Thus, larger studies using more sensitive imaging biomarkers are warranted in humans in order to discover whether some of the improvements seen after STN DBS can be attributed to changes in DAergic levels.…”