Consequences of Altered Dopamine Signaling on the Serotonin Circuitry in Drosophila
Cognitive, Systems and Behavioural Neurobiology
Final Report Abstract
Parkinson’s disease (PD) results from a progressive degeneration of the dopaminergic nigrostriatal system, ultimately leading to a decline in movement control associated with resting tremor, rigidity and postural instability. A combination of environmental factors and notyet determined individual genetic susceptibility is the suspected cause. Degeneration of dopaminergic neurons within the substantia nigra pars compacta was shown to have direct repercussions on the plasticity modulation of the neurons that release serotonin (5-HT). Tyrosine Hydroxylase (TH) deficient Drosophila that are unable to produce dopamine (DA) in the central nervous system show a variety of behavioural deficits that are comparable with the phenotypes of TH mutant mice. Our own detailed anatomical studies of the nervous system of these TH mutant flies revealed changes in the innervation pattern of 5-HT producing neurons, such as hyper-innervation in brain regions that, under normal conditions, are mainly innervated by DA neurons. The observed DA-dependent changes in 5-HT neuron anatomy prompted us to assume direct or indirect communication between DA producing cells and 5-HT producing neurons. The originally proposed project aimed at the identification of such circuit connections to understand how these may be altered under defective dopamine neuron signalling properties. For the unambiguous detection of possible alterations, it is crucial to obtain a precise knowledge about the neuronal circuits of modulatory neurons under normal conditions. Monoamine neurons have a relatively small and clear number and recognizable morphology. This means that it should be feasible to identify individual neurons in the electron microscopy (EM) dataset nearly completely. In a first step we have helped the Janalia FlyEM project to identify 31% of monoamine neurons in the EM connectome dataset. After the current project we have now reached a coverage of 96% of all monoamine neurons. We identified candidate neurons by the exhaustive screening of EM and light-microscopy single neuron images and comparison with multiple samples of antibody labeling related to each monoamine transmitter (10 samples for each). For the final unambiguous identification of neurons, we teamed up with the DFG funding CRC1451, which enabled the use of the threedimensional Virtual Reality system called CAVE in our university for neuron analysis. Our analysis revealed how DA neurons and 5-HT producing neurons overlap or segregate and where in the brain they form synaptic connections. Thanks to the near-complete mapping of the monoamine neurons, we have identified a pair of specific DA neurons that innervate the antler region, a symmetric neuropil located in the posterior dorsomedial part of the fly brain. We ectopically expressed human α-synuclein (hα-syn) in these neurons to mimic the situation of PD and examined the distribution of their presynaptic sites by co-expressing synaptic vesicle-targeted Syt::HA. We found that, even though the neurons have symmetric arborizations on both sides of the brain, synapses on the left side get depleted more severely than on the left side, which is reminiscent of the asymmetric synapse depletion symptoms in human PD patients. This represents the first example of unilateral predominance in an invertebrate model of PD.
Publications
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Asymmetric Presynaptic Depletion of Dopamine Neurons in a Drosophila Model of Parkinson’s Disease. International Journal of Molecular Sciences, 24(10), 8585.
Zhang, Jiajun; Lentz, Lucie; Goldammer, Jens; Iliescu, Jessica; Tanimura, Jun & Riemensperger, Thomas Dieter
