Our team investigates the mechanisms of cellular interactions, neurodegeneration and neuroplasticity, in particular in the context of basal ganglia-related pathologies.

FOR BEGINNERS

Neurodegeneration is a progressive pathological process that triggers dysfunction and death of nerve cells. Many neurodegenerative disorders, including Parkinson’s disease, occur as a result of neurodegenerative processes whose causes are not fully elucidated. Understanding the pathological mechanisms leading to neurodegeneration (pathogenesis) and its consequences on the functioning of neural networks is essential for the development of curative or preventive treatments.

Progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc delineated by dotted lines) after dysfunction of excitatory amino acid transporters

Neuroplasticity, also known as brain plasticity, refers to the capacity of the nervous system to adapt in response to experience and to internal or external stimulations by modifying the interactions between nerve cells (such as changes in the connections between neurons called “synapses” or in the activity) or by generating new nerve cells. This phenomenon is not limited to embryonic or post-natal development, but occurs all along the life. Neuroplasticity has been notably involved in learning and memory processes. It also occurs under pathological conditions or in response to chronic treatments. Such adaptive changes can either represent compensatory mechanisms counteracting the deficits triggered by neuronal dysfunction or death, or, on the contrary, participate in or even aggravate the deficits.

Parkinson’s disease is a progressive neurodegenerative disorder with high prevalence (second most common neurodegenerative disease after Alzheimer’s disease). The disease usually begins between the ages of 45 and 70. It is characterized by a triad of severe motor symptoms but is also associated with a set of non-motor symptoms. One main neuropathological feature of Parkinson’s disease is the loss of neurons located in a deep brain region, called locus niger or substantia nigra. These neurons, which use dopamine as a neurotransmitter, notably regulate the activity of the basal ganglia, a set of brain structures involved in motor learning and movement control. The neurodegenerative process will lead to compensatory hyperactivity of dopamine neurons not yet affected, but also to a cascade of structural and functional reorganizations within the basal ganglia network and interacting brain structures, which generates the cardinal symptoms of the disease (pathophysiology). Long-term treatments can also trigger adaptive changes underlying the maintenance of their beneficial effects or, on the contrary, the appearance of side effects. Characterizing these adaptive changes in Parkinson’s disease and in response to its current treatments could provide a basis for the development of future therapeutic strategies. Our primary aim is to better understand the normal and pathological functioning of the basal ganglia with a focus on Parkinson’s disease, but also in the context of autism spectrum disorders in collaboration with Laurent Fasano’s team at the Institute, through studies on animal models (rat, mouse, Drosophila). Our work also concerns other pathologies, such as Charcot-Marie-Tooth disease or Alzheimer’s disease.

Visualisation of nigral dopaminergic neurons and their astrocytic environment by dual immunodetection of the dopamine synthetizing enzyme tyrosine hydroxylase and of the glial excitatory aminoacid transporter GLT1
Illustration: Ⓒ Jean-Pierre Kessler, IBDM, Marseille

FOR SPECIALISTS

The team combines multilevel expertise and skills to study synaptic transmission, neurodegeneration and neuroplasticity in the adult brain, using rodent and Drosophila models. The central interest is on basal ganglia (BG)-related functions and pathologies, with focus on the pathophysiology and treatment of Parkinson’s disease (PD), which is characterized by the degeneration of the nigrostriatal dopaminergic neurons. Ongoing research lines have three main objectives:

1. Gain knowledge on the anatomofunctional organization of the BG network and its remodeling in pathological condition, which may help design novel symptomatic treatment; the current work is centered on striatal cholinergic interneurons and corticostriatal synaptic function/plasticity.
   

   Optogenetic control of striatal cholinergic interneurons.
   Double labeling, in the striatum of transgenic mice, of the striatal output neurons expressing the dopamine D1 receptor (fused to tdTomato; red fluorescence) and the cholinergic interneurons in which expression of halorhodopsin (fused to EYFP; green fluorescence) has been driven to allow their photo-inhibition. The electrophysiological trace illustrates the interruption of the spontaneous spiking of one cholinergic interneuron obtained when amber light is delivered in vivo into the striatum of these mice.
   Ⓒ Nicolas Maurice, IBDM, Marseille

2.  Identify molecular players in neuronal death processes or defense pathways against cellular stress that may represent new targets for disease-modifying strategies. Particular focus is made on the mechanisms regulating autophagy, mitochondrial dynamics and mitochondrial quality control via mitophagy, which are main players in neurodegenerative diseases. This research is performed in the context of PD, but also of Alzheimer’s disease and Charcot-Marie-Tooth disease type 2A.
3. Identify disease-relevant anatomical targets for the surgical treatment by deep brain stimulation and evaluate the neuroprotective potential of this neurosurgical therapy.

We are also deeply involved in two collaborative projects developed by other IBDM teams.
One project aims at characterizing the neuronal substrates of the autistic syndrome linked to haploinsufficiency of TSHZ3, the gene encoding the transcription factor TSHZ3 (Laurent Fasano’s team). We are characterizing several transgenic mouse models with targeted conditional deletion of Tshz3 in components of the corticostriatal circuitry to define “where” and “when” the loss of Tshz3 is crucial for developing the core symptoms of ASD, by combining molecular, cellular, electrophysiological and behavioral approaches.

Retrograde transynaptic tracing of a striatal spiny neuron and of the cortical neurons projecting to the striatum using rabies virus
Ⓒ Pascal Salin, IBDM, Marseille

The other project aims at improving the efficacy and safety of the cell-based replacement therapy for PD using human induced pluripotent stem cells (hiPSCs) (Rosana Dono in Flavio Maina’s team). We are currently evaluating the potential of regulating the levels of glypican 4, a signaling modulator, as a strategy to foster hiPSCs differentiation towards the disease-relevant cell type, namely ventral midbrain dopamine neuron, and reduce their propensity to develop tumors upon brain transplantation in a rat PD model at different stages of in vitro differentiation.

Our approach combines the use or development of relevant experimental models in rodents (chronic deep brain stimulation, cell specific ablation, optogenetic or chemogenetic modulation of neuronal activity) with a variety of analytic tools, including behavioral tests, functional anatomy, tract-tracing, electrophysiology (on brain slices and in vivo), neurochemistry, and is implemented with genetics, imaging and molecular biology in Drosophila models.

INPI n° 2942412 : Microstimulateur cerebral d’accessibilité aisée et méthode d’installation d’un tel microstimulateur (co-inventors: P. Salin, C. Forni, O. Mainard, C. Melon, E. Richard, and D. Goguenheim) CNRS Patent.