Altered glutamate release in the dorsal striatum of the MitoPark mouse model of Parkinson's disease

Abstract

Mitochondrial dysfunction has been implicated in the degeneration of dopamine (DA) neurons in Parkinson’s disease (PD). In addition, animal models of PD utilizing neurotoxins, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have shown that these toxins disrupt mitochondrial respiration by targeting complex I of the electron transport chain, thereby impairing DA neurons in these models. A MitoPark mouse model was created to mimic the mitochondrial dysfunction observed in the DA system of PD patients. These mice display the same phenotypic characteristics as PD, including accelerated decline in motor function and DAergic systems with age. Previously, these mice have responded to L-Dopa treatment and develop L-Dopa induced dyskinesia (LID) as they age. A potential mechanism involved in the formation of LID is greater glutamate release into the dorsal striatum as a result of altered basal ganglia neurocircuitry due to reduced nigrostriatal DA neurotransmission. Therefore, the focus of this study was to assess various indicators of glutamate neurotransmission in the dorsal striatum of MitoPark mice at an age in which nigrostriatal DA has degenerated. At 28 weeks of age, MitoPark mice had, upon KCl stimulation, greater glutamate release in the dorsal striatum compared to control mice. In addition, uptake kinetics were slower in MitoPark mice. These findings were coupled with reduced expression of the glutamate re-uptake transporter, GLT-1, thus providing an environment suitable for glutamate excitotoxic events, leading to altered physiological function in these mice.

Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice

“…Reduced GLT-1 expression contributes to the comorbidity of depression and anxiety 10 and aggravates effects of traumatic injuries 11 . The dysregulation of GLT-1 is associated with neuronal damage in neurodegenerative diseases 12 .…”

Characterization of Nonmotor Symptoms in the MitoPark Mouse Model of Parkinson’s Disease

“…At 6-10 wks, impaired electrophysiological parameters were found in dopaminergic neurons, and increased L-type calcium channel mRNA and PK2 protein expression were observed in MitoPark mice versus their littermate controls 52,32,53 . At 28-30 wks, increased astrocyte marker GFAP, greater striatal glutamate release, and white matter MRI changes were identified 54 . Also at 30 wks, MRI changes indicative of iron accumulation were found in the substantia nigra 54 .…”

PDZ Scaffold Protein CAL Couples with Metabotropic Glutamate Receptor 5 to Protect Against Cell Apoptosis and Is a Potential Target in the Treatment of Parkinson's Disease

“…The interacting proteins, such as adenosine receptor A 2A or N-methyl-D-aspartic acid (NMDA) receptor, regulate mGluR5 function, and simultaneous blocking of these proteins and mGluR5 results in the reciprocal synergistic therapeutic effect in PD [54,55]. Moreover, dopaminergic degeneration in PD models results in increased glutamate release in the dorsal striatum [56,57], and blockade of this excess excitatory drive may alternatively modulate excitatory transmission in the basal ganglia to attenuate parkinsonian symptoms [5]. This evidence suggests that the identification of the regulatory factors to target mGluR5 might provide a novel therapeutic strategy for PD.…”