Significant advances have been made uncovering the factors that render neurons vulnerable in Parkinson's disease (PD). However, the critical pathogenic events leading to cell loss remain poorly understood, complicating the development of disease-modifying interventions. Given that the cardinal motor symptoms and pathology of PD involve the loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc), a majority of the work in the PD field has focused on this specific neuronal population. PD however, is not a disease of DA neurons exclusively: pathology, most notably in the form of Lewy bodies and neurites, has been reported in multiple regions of the central and peripheral nervous system, including for example the locus coeruleus, the dorsal raphe nucleus and the dorsal motor nucleus of the vagus. Cell and/or terminal loss of these additional nuclei is likely to contribute to some of the other symptoms of PD and, most notably to the non-motor features. However, exactly which regions show actual, well-documented, cell loss is presently unclear. In this review we will first examine the strength of the evidence describing the regions of cell loss in idiopathic PD, as well as the order in which this loss occurs. Secondly, we will discuss the neurochemical, morphological and physiological characteristics that render SNc DA neurons vulnerable, and will examine the evidence for these characteristics being shared across PD-affected neuronal populations. The insights raised by focusing on the underpinnings of the selective vulnerability of neurons in PD might be helpful to facilitate the development of new disease-modifying strategies and improve animal models of the disease.

While current effective therapies are available for the symptomatic control of PD, treatments to halt the progressive neurodegeneration still do not exist. Loss of dopamine neurons in the SNc and dopamine terminals in the striatum drive the motor features of PD. Multiple lines of research point to several pathways which may contribute to dopaminergic neurodegeneration. These pathways include extensive axonal arborization, mitochondrial dysfunction, dopamine's biochemical properties, abnormal protein accumulation of α‐synuclein, defective autophagy and lysosomal degradation, and synaptic impairment. Thus, understanding the essential features and mechanisms of dopaminergic neuronal vulnerability is a major scientific challenge and highlights an outstanding need for fostering effective therapies against neurodegeneration in PD. This article, which arose from the Movement Disorders 2018 Conference, discusses and reviews the possible mechanisms underlying neuronal vulnerability and potential therapeutic approaches in PD. © 2019 International Parkinson and Movement Disorder Society

30Chemical neurotransmission in the brain typically occurs through synapses, which are structurally 31 and functionally defined as sites of close apposition between an axon terminal and a postsynaptic 32 domain. Ultrastructural examinations of axon terminals established by monoamine neurons in 33 the brain often failed to identify a similar tight pre-and postsynaptic coupling, giving rise to the 34 concept of "diffuse" or "volume" transmission. Whether this results from intrinsic properties of 35 such modulatory neurons remains undefined. Using an efficient co-culture model, we find that 36 dopaminergic neurons establish an axonal arbor that is distinctive compared to glutamatergic or 37 GABAergic neurons in both size and propensity of terminals to avoid direct contact with target 38 neurons. Furthermore, while most dopaminergic varicosities express key proteins involved in 39 exocytosis such as synaptotagmin 1, only 20% of these are synaptic. The active zone protein 40 bassoon was found to be enriched in a subset of dopaminergic terminals that are in proximity to 41 a target cell. Irrespective of their structure, a majority of dopaminergic terminals were found to 42 be active. Finally, we found that the presynaptic protein Nrxn-1 SS4and the postsynaptic protein 43 NL-1 AB , two major components involved in excitatory synapse formation, play a critical role in the 44 formation of synapses by dopamine neurons. Taken together, our findings support the idea that 45 dopamine neurons in the brain are endowed with a distinctive developmental program that leads 46 them to adopt a fundamentally different mode of connectivity, compared to glutamatergic and 47 GABAergic neurons involved in fast point-to-point signaling. 48 49 51 SIGNIFICANCE STATEMENT 52Midbrain dopamine (DA) neurons regulate circuits controlling movement, motivation, and 53 learning. The axonal connectivity of DA neurons is intriguing due to its hyperdense nature, with a 54 particularly large number of release sites, most of which not adopting a classical synaptic 55 structure. In this study, we provide new evidence highlighting the unique ability of DA neurons to 56 establish a large and heterogeneous axonal arbor with terminals that, in striking contrast with 57 glutamate and GABA neurons, actively avoid contact with the target cells. The majority of synaptic 58 and non-synaptic terminals express proteins for exocytosis and are active. Finally, our finding 59 suggests that, NL-1 A+B and Nrxn-1 SS4-, play a critical role in the formation of synapses by DA 60 neurons. 61 62 postsynaptic coupling at most release sites, giving rise to the concept of "diffuse" or "volume" 85 transmission, whereby neurotransmitter release from non-synaptic axon terminals leads to 86 activation of metabotropic receptors on target cells located at a distance, within a sphere of a 87 few tens of microns (17)(18)(19)(20)(21)(22)(23)(24). 88The molecular mechanisms determining the ability of DA neurons to establish synaptic 89 and non-synaptic terminals are presently unknown. M...

Chemical neurotransmission typically occurs through synapses. Previous ultrastructural examinations of monoamine neuron axon terminals often failed to identify a pre-and postsynaptic coupling, leading to the concept of "volume" transmission. Whether this results from intrinsic properties of these neurons remains undefined. We find that dopaminergic neurons in vitro establish a distinctive axonal arbor compared to glutamatergic or GABAergic neurons in both size and propensity of terminals to avoid direct contact with target neurons.While most dopaminergic varicosities are active and contain exocytosis proteins like synaptotagmin 1, only ~20% of these are synaptic. The active zone protein bassoon was found to be enriched in dopaminergic terminals that are in proximity to a target cell. Finally, we found that the proteins neurexin-1α SS4− and neuroligin-1 A+B play a critical role in the formation of synapses by dopamine

Initiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual’s sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes.