Increased vulnerability of nigral dopamine neurons after expansion of their axonal arborization size through D2 dopamine receptor conditional knockout

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Rare genetic mutations in genes such as Parkin, Pink1, DJ-1, α-synuclein, LRRK2 and GBA are found to be responsible for the disease in about 15% of the cases. A key unanswered question in PD pathophysiology is why would these mutations, impacting basic cellular processes such as mitochondrial function and neurotransmission, lead to selective degeneration of SNc DA neurons? We previously showed in vitro that SNc DA neurons have an extremely high rate of mitochondrial oxidative phosphorylation and ATP production, characteristics that appear to be the result of their highly complex axonal arborization. To test the hypothesis in vivo that axon arborization size is a key determinant of vulnerability, we selectively labeled SNc or VTA DA neurons using floxed YFP viral injections in DAT-cre mice and showed that SNc DA neurons have a much more arborized axon than those of the VTA. To further enhance this difference, which may represent a limiting factor in the basal vulnerability of these neurons, we selectively deleted in mice the DA D2 receptor (D2-cKO), a key negative regulator of the axonal arbour of DA neurons. In these mice, SNc DA neurons have a 2-fold larger axonal arborization, release less DA and are more vulnerable to a 6-OHDA lesion, but not to α-synuclein overexpression when compared to control SNc DA neurons. This work adds to the accumulating evidence that the axonal arborization size of SNc DA neurons plays a key role in their vulnerability in the context of PD.

Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?

“…SNc dopamine (DA) neurons exhibit elevated rates of oxidative phosphorylation, showing a threefold increase in ATP production and ROS generation in SNc compared to VTA neurons (Pacelli et al, 2015). A higher density of mitochondria in SNc axonal arbor compared to VTA indicates a higher energy requirement for the functioning of SNc neurons (Pacelli et al, 2015;Giguère et al, 2019).…”

“…At cellular level, the glutamate concentration is affected by differential expression of glutamatergic and neuropeptide receptors. Additionally, extensive arboreal structures can tend to hyperexcitation of glutamate receptors even at the physiological levels of glutamate concentration (Pahapill and Lozano, 2000;Heng et al, 2009;Pacelli et al, 2015;Estakhr et al, 2017;Wang and Reddy, 2017;Giguère et al, 2019;Gregory et al, 2019). Finally, at systems level, overexcitation from pathogenic nuclei can lead to calcium accumulation in ER and mitochondria, which in turn results in neurodegeneration (Rodriguez et al, 1998;Hansson et al, 1999;Pahapill and Lozano, 2000;Kawahara et al, 2003;Vaarmann et al, 2013;Muddapu et al, 2019).…”

A Computational Model of Levodopa-Induced Toxicity in Substantia Nigra Pars Compacta in Parkinson’s Disease

“…The goal of this computational study is to develop a model of SNc-striatum, which helps us in understanding LDOPA-induced toxicity in SNc neurons under energy deficiency conditions. From both homogeneous and heterogeneous energy deficiency results, it suggests that SNc (axonal) terminals are more vulnerable to energy imbalance when compared to SNc cell bodies (somas) which was observed experimentally, where injury is initiated at axonal terminals (Burré et al, 2010;Cheng et al, 2010;Giguère et al, 2019;Wong et al, 2019). The higher positive currents from STN might lead to excitotoxic loss of SNc somas ( Figure 5A, blue bar), and increased ROS production might lead to increased SNc terminal loss ( Figure 5A, orange bar).…”

“…Recently, a modeling study has been proposed where PD is described to be resulting from the metabolic deficiency in SNc (Muddapu et al, 2019;Muddapu and Chakravarthy, 2020a). The vulnerable cells of SNc are projection neurons with large axonal arbors of complex morphologies, requiring a huge amount of energy to maintain information processing activities (Bolam and Pissadaki, 2012;Giguère et al, 2019;Muddapu et al, 2020;Pissadaki and Bolam, 2013). Due to huge energy requirements, SNc neurons exhibit higher basal metabolic rates and higher oxygen consumption rate, which result in oxidative stress (Pacelli et al, 2015).…”

Direct dopamine terminal regulation by local striatal microcircuitry

“…Aside from acute regulation of terminal excitability and associated release, activation of D2Rs has been shown to drive posttranslational modifications to other regulators, such as DAT and vesicular monoamine transporter‐2 (VMAT2), leading to lasting alterations in transporter function and associated repackaging efficiency (Belin, Deroche‐Gamonet, & Jaber, 2007; Meiergerd, Patterson, & Schenk, 1993), an effect that alters the timing of dopamine release. Similarly, chronic activation of D2Rs can also induce morphological changes in dopaminergic axon growth and alterations in plasticity across multiple striatal subregions (Fasano, Kortleven, & Trudeau, 2010; Giguère et al., 2019; Parish, Finkelstein, Drago, Borrelli, & Horne, 2001; Parish et al., 2002; Tripanichkul, Stanic, Drago, Finkelstein, & Horne, 2003). These changes have important implications for subsequent terminal release events and dopamine‐mediated plasticity of other cell types across the brain as well.…”