TEAM
Cellular interactions, neurodegeneration and neuroplasticity
Group leader : L. Kerkerian – Le Goff
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:
- 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 - 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.
- 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.
Selected publications
PUBLICATION
October 12th, 2020
Golgi staining-like retrograde labeling of brain circuits using rabies virus: Focus onto the striatonigral neurons
PUBLICATION
June 12th, 2020
Reply to: Letter to the Editor by Martínez-Fernández
PUBLICATION
April 2nd, 2020
Subthalamic Nucleus Stimulation Impairs Motivation: Implication for Apathy in Parkinson's Disease
PUBLICATION
March 14th, 2020
Glutamate transporter 1-expressing glia in the rat substantia nigra-Morphometric analysis and relationships to synapses
PUBLICATION
January 21st, 2020
Construct Validity and Cross Validity of a Test Battery Modeling Autism Spectrum Disorder (ASD) in Mice.
PUBLICATION
December 13th, 2019
Striatal Cholinergic Interneurons: How to Elucidate Their Function in Health and Disease
PUBLICATION
October 3rd, 2019
PlexinD1 and Sema3E determine laminar positioning of heterotopically projecting callosal neurons.
PUBLICATION
August 15th, 2019
Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder-like Behavior
PUBLICATION
January 3rd, 2019
Chronic fornix deep brain stimulation in a transgenic Alzheimer's rat model reduces amyloid burden, inflammation, and neuronal loss
PUBLICATION
January 3rd, 2019
Opto nongenetics inhibition of neuronal firing
PUBLICATION
September 26th, 2016
TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons.
PUBLICATION
August 31st, 2016
Involvement of Striatal Cholinergic Interneurons and M1 and M4 Muscarinic Receptors in Motor Symptoms of Parkinson's Disease.
PUBLICATION
July 2nd, 2016
SLC35D3 increases autophagic activity in midbrain dopaminergic neurons by enhancing BECN1-ATG14-PIK3C3 complex formation
PUBLICATION
June 7th, 2016
LAMP5 Fine-Tunes GABAergic Synaptic Transmission in Defined Circuits of the Mouse Brain.
PUBLICATION
March 1st, 2016
Metabolic, synaptic and behavioral impact of 5-week chronic deep brain stimulation in hemiparkinsonian rats.
PUBLICATION
February 3rd, 2016
Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow-progression model of Huntington's disease
PUBLICATION
December 1st, 2015
Endocannabinoids Mediate Muscarinic Acetylcholine Receptor-Dependent Long-Term Depression in the Adult Medial Prefrontal Cortex
PUBLICATION
November 16th, 2015
Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease.
PUBLICATION
September 1st, 2015
Striatal Cholinergic Interneurons Control Motor Behavior and Basal Ganglia Function in Experimental Parkinsonism
PUBLICATION
April 14th, 2015
Differential organization of cortical inputs to striatal projection neurons of the matrix compartment in rats.
PUBLICATION
March 1st, 2015
Progressive brain metabolic changes under deep brain stimulation of subthalamic nucleus in parkinsonian rats.
PUBLICATION
June 17th, 2014
Reducing Glypican-4 in ES Cells Improves Recovery in a Rat Model of Parkinson's Disease by Increasing the Production of Dopaminergic Neurons and Decreasing Teratoma Formation.
PUBLICATION
June 11th, 2014
Oxygen glucose deprivation-induced astrocyte dysfunction provokes neuronal death through oxidative stress.
PUBLICATION
June 6th, 2014
Cellular and Behavioral Outcomes of Dorsal Striatonigral Neuron Ablation: New Insights into Striatal Functions.
PUBLICATION
May 24th, 2014
Distinct effects of mGlu4 receptor positive allosteric modulators at corticostriatal vs. striatopallidal synapses may differentially contribute to their antiparkinsonian action.
PUBLICATION
May 15th, 2014
Tyrosine hydroxylase expression and activity in nigrostriatal dopaminergic neurons of MPTP-treated mice at the presymptomatic and symptomatic stages of parkinsonism
PUBLICATION
May 12th, 2014
Progressive Parkinsonism by acute dysfunction of excitatory amino acid transporters in the rat substantia nigra
PUBLICATION
January 1st, 2014
Spatial learning, monoamines and oxidative stress in rats exposed to 900 MHz electromagnetic field in combination with iron overload
PUBLICATION
April 1st, 2013
Striatal molecular signature of subchronic subthalamic nucleus high frequency stimulation in parkinsonian rat.
PUBLICATION
February 22nd, 2013
Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia.
PUBLICATION
December 11th, 2012
The nucleus accumbens 5-HTR₄-CART pathway ties anorexia to hyperactivity.
PUBLICATION
December 11th, 2012
The nucleus accumbens 5-HTR₄-CART pathway ties anorexia to hyperactivity.
PUBLICATION
July 30th, 2012
Portable microstimulator for chronic deep brain stimulation in freely moving rats.
PUBLICATION
April 1st, 2012
Antiparkinsonian action of a selective group III mGlu receptor agonist is associated with reversal of subthalamonigral overactivity.
PUBLICATION
June 1st, 2011
High frequency stimulation of the subthalamic nucleus impacts adult neurogenesis in a rat model of Parkinson's disease.
PUBLICATION
December 15th, 2010
The added value of rabies virus as a retrograde tracer when combined with dual anterograde tract-tracing.
PUBLICATION
October 1st, 2010
Deep brain stimulation mechanisms: beyond the concept of local functional inhibition.
PUBLICATION
August 1st, 2010
Forelimb dyskinesia mediated by high-frequency stimulation of the subthalamic nucleus is linked to rapid activation of the NR2B subunit of N-methyl-D-aspartate receptors.
PUBLICATION
July 21st, 2010
Deep brain stimulation of the center median-parafascicular complex of the thalamus has efficient anti-parkinsonian action associated with widespread cellular responses in the basal ganglia network in a rat model of Parkinson's disease.
PUBLICATION
June 1st, 2010
[Acetylcholinesterase inhibitors in Alzheimer's disease: further comments on their mechanisms of action and therapeutic consequences].
PUBLICATION
April 23rd, 2010
Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury.
PUBLICATION
January 1st, 2010
Ciliary neurotrophic factor protects striatal neurons against excitotoxicity by enhancing glial glutamate uptake.
PUBLICATION
January 1st, 2010
Downstream mechanisms triggered by mitochondrial dysfunction in the basal ganglia: from experimental models to neurodegenerative diseases.
PUBLICATION
January 1st, 2010
Effects of GPi and STN inactivation on physiological, motor, cognitive and motivational processes in animal models of Parkinson's disease.
PUBLICATION
December 1st, 2009
Rationale for targeting the thalamic centre-median parafascicular complex in the surgical treatment of Parkinson's disease.
PUBLICATION
October 30th, 2009
Cocaine-induced stereotypy is linked to an imbalance between the medial prefrontal and sensorimotor circuits of the basal ganglia.
PUBLICATION
October 23rd, 2009
Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism.
PUBLICATION
October 1st, 2009
Mechanisms contributing to the phase-dependent regulation of neurogenesis by the novel antidepressant, agomelatine, in the adult rat hippocampus.
PUBLICATION
October 1st, 2009
Different functional basal ganglia subcircuits associated with anti-akinetic and dyskinesiogenic effects of antiparkinsonian therapies.
PUBLICATION
September 1st, 2009
Deep brain stimulation in neurological diseases and experimental models: from molecule to complex behavior.
PUBLICATION
June 1st, 2009
Changes to interneuron-driven striatal microcircuits in a rat model of Parkinson's disease.
PUBLICATION
May 1st, 2009
Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson's disease treatment.
PUBLICATION
February 18th, 2009
Role of glutamate transporters in corticostriatal synaptic transmission.
PUBLICATION
February 16th, 2009
Impact of surgery targeting the caudal intralaminar thalamic nuclei on the pathophysiological functioning of basal ganglia in a rat model of Parkinson's disease.
PUBLICATION
December 24th, 2008
Importance of circadian rhythmicity in the cholinergic treatment of Alzheimer's disease: focus on galantamine*.
PUBLICATION
July 24th, 2008
High-resolution neuroanatomical tract-tracing for the analysis of striatal microcircuits.
PUBLICATION
June 1st, 2008
Plasma membrane expression of the neuronal glutamate transporter EAAC1 is regulated by glial factors: evidence for different regulatory pathways associated with neuronal maturation.
PUBLICATION
April 1st, 2008
Preferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunction.
PUBLICATION
October 1st, 2007
Na(v)1.7 and Na(v)1.3 are the only tetrodotoxin-sensitive sodium channels expressed by the adult guinea pig enteric nervous system.
PUBLICATION
February 28th, 2007
High-frequency stimulation of the subthalamic nucleus potentiates L-DOPA-induced neurochemical changes in the striatum in a rat model of Parkinson's disease.
PUBLICATION
November 17th, 2006
Deficits of glutamate transmission in the striatum of experimental hemiballism.
PUBLICATION
September 1st, 2006
Chronic high-frequency stimulation of the subthalamic nucleus and L-DOPA treatment in experimental parkinsonism: effects on motor behaviour and striatal glutamate transmission.
PUBLICATION
August 1st, 2006
The neuronal excitatory amino acid transporter EAAC1/EAAT3: does it represent a major actor at the brain excitatory synapse?
PUBLICATION
July 1st, 2006
Glutamate leakage from a compartmentalized intracellular metabolic pool and activation of the lipoxygenase pathway mediate oxidative astrocyte death by reversed glutamate transport.
PUBLICATION
May 31st, 2006
Ciliary neurotrophic factor activates astrocytes, redistributes their glutamate transporters GLAST and GLT-1 to raft microdomains, and improves glutamate handling in vivo.
PUBLICATION
October 1st, 2005
Transient hippocampal down-regulation of Kv1.1 subunit mRNA during associative learning in rats.
PUBLICATION
July 7th, 2005
Enhanced delivery of gamma-secretase inhibitor DAPT into the brain via an ascorbic acid mediated strategy.
PUBLICATION
March 1st, 2004
Glial soluble factors regulate the activity and expression of the neuronal glutamate transporter EAAC1: implication of cholesterol.
PUBLICATION
September 10th, 2003
Metabotropic glutamate 5 receptor blockade alleviates akinesia by normalizing activity of selective basal-ganglia structures in parkinsonian rats.
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.