Striatal glutamate induces retrograde excitotoxicity and neuronal degeneration of intralaminar thalamic nuclei: their potential relevance for Parkinson's disease

Abstract

An over-stimulation of nigral glutamate (GLU) receptors has been proposed as a cause of the progression of the dopamine (DA) cell degeneration (excitotoxicity) which characterizes Parkinson's disease. The possible toxic action of striatal GLU (retrograde excitotoxicity) on these cells, and on other neurons which innervate the striatum and which also degenerate in Parkinson's disease (thalamostriatal cells of the intralaminar thalamic nuclei), is still practically unexplored. The retrograde excitotoxicity of striatal GLU on DAergic mesostriatal and GLUergic thalamostriatal cells was tested here by studying these cells 6 weeks after striatal perfusion of GLU by reverse microdialysis. GLU perfusion induced the striatal denervation of thalamic inputs (as revealed by vesicular glutamate transporter 2) and the remote degeneration of intralaminar neurons. In both centres, these effects were accompanied by microglial activation. Similar responses were not observed for nigrostriatal neurons, which showed no dopaminergic striatal denervation, no microglial activation in the substantia nigra and no changes in the number of dopaminergic cells in the substantia nigra. The inhibition of DAergic transmission increased the extrasynaptic GLU levels in the striatum (evaluated by microdialysis), an effect observed after the local administration of agonists and antagonists of DAergic transmission, and after the peripheral administration of levodopa (which increased the DA and decreased the GLU levels in the striatum of rats with an experimental DAergic denervation of this centre). The data presented show that striatal GLU induced a retrograde excitotoxicity which did not affect all striatal inputs in the same way and which could be involved in the cell degeneration of the intralaminar nuclei of the thalamus generally observed in Parkinson's disease.

Characterization of retinal architecture in Parkinson's disease

“…Significant reduction in IPL and INL volume is supported by the loss of tyrosine hydroxylase-positive dopaminergic fibers and amacrine cells in the IPL and INL [22]. Furthermore, it is possible that impoverished dopaminergic input contributes to abnormal production of glutamate and degeneration of these selected fibers in the retina [26].…”

Parkinson's disease as a result of aging

“…In addition, PD neurodegeneration has been found in neurons not directly interacting with the snDAn, such as those of the myenteric plexus or the olfactory bulb. The mechanisms involved in the loss of non-DA neurons have been little studied, and there is evidence supporting the idea that PD degeneration begins in non-DA neurons and then progresses to DA neurons (Braak et al ., 2003; Ferrer et al ., 2011), but also supporting the possibility that the degeneration of non-DA neurons could be induced by the previous degeneration of DA neurons (Morales et al ., 2013a,b). In any case, the parkinsonian degeneration observed in most non-DA neurons has also been found in the healthy aged brain (Iversen et al ., 1983; Baker et al ., 1989; Manaye et al ., 1995; Arango et al ., 1996; Ransmayr et al ., 2000), which also presents the cytosolic aggregates reported in the PD brain (e.g.…”

“…Astrocytes are involved in a variety of physiological functions (Benarroch, 2009; Sofroniew & Vinters, 2010; Rodriguez et al ., 2012) and whose deterioration has been linked to both PD and aging (Raivich et al ., 1999; Sofroniew & Vinters, 2010; Belanger et al ., 2011; Rodriguez et al ., 2012; Morales et al ., 2013a). These cells may behave in an opposing manner, promoting damage or providing protection to neurons.…”

“…that protect the DAn from damage (Lin et al ., 1993; Saavedra et al ., 2006; Deierborg et al ., 2008). In addition, astrocytes remove toxic molecules from the extracellular medium, including the α-synuclein that has escaped from axon terminals (which prevents its aggregation in DAn) (Braak et al ., 2007; Song et al ., 2009; Lee et al ., 2010) and glutamate released from glutamatergic neurons (which prevents its excitotoxic action) (Rodriguez et al ., 2012; Morales et al ., 2013a,b). These protective activities decrease during aging.…”

Assessment of Amino Acid Neurotransmitters in Rat Brain Microdialysis Samples by High-Performance Liquid Chromatography with Coulometric Detection

“…[1,2] These neurotransmitters are major players in variety of normal brain functions and correlate with neurodegenerative and neuropsychiatric disorders such as Huntington's disease, [3] Alzheimer's disease, [4] schizophrenia, [5] ischemic stroke, [6] hypoglycemia, [7] Parkinson's disease, [4,8] Down's syndrome, [9] etc… AA neurotransmitters are released from presynaptic neurons to the synaptic cleft and achieve their functions by coupling with their receptors on postsynaptic neurons. The analysis of AA neurotransmitters in the extracellular space is important in basic, as well as, clinical brain research.…”