TEAM

Cellular interactions, neurodegeneration and neuroplasticity

Group leader : L. Kerkerian – Le Goff

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Our team aims at better understanding the mechanisms of cellular interactions, neurodegeneration and neuroplasticity in the context of Parkinson’s disease.

FOR BEGINNERS

Neurodegeneration designs the progressive pathological mechanisms leading to 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 those mechanisms is essential for the development of preventive or curative treatments.

This picture from Lydia's lab studying neuroplasticity shows the adult neurogenesis n the hippocampus.

Adult neurogenesis in the hippocampus: morphology of newborn neuroblasts labeled by DCX (doublecortin) immunocytochemistry.

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 (changes in the connections 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. As an example, the production of new neurons, a process called neurogenesis, is maintained in adulthood, although being restricted to a limited number of brain regions. Neuroplasticity has been notably involved in learning and memory processes. It also occurs under pathological conditions and can either represent compensatory mechanisms counteracting the deficits triggered by neuronal dysfunction or death, or, on the contrary, contribute to or even exacerbate the deficits.

Lydia's lab study Parkison's disease and dopaminergic neurons

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

Parkinson’s disease is a neurodegenerative disorder with high prevalence (second after Alzheimer’s disease), characterized by severe motor symptoms. These symptoms are resulting from the death of a population of neurons located in a deep brain region called locus niger (or “substantia nigra”) using dopamine as a neurotransmitter. Dopamine deficiency triggers dysfunction in the structures innervated by these neurons, in particular the basal ganglia, a set of structures notably involved in motor learning and movement control. Parkinson’s disease is more common in the elderly, with most cases occurring after the age of 60. The degenerative process is associated with adaptive changes in neuronal networks, including a compensatory overactivity of remaining dopamine neurons and functional or structural remodelling in other neuronal systems. The treatments at long term can also trigger adaptive phenomena underlying the maintenance of their beneficial effects or, on the contrary, the appearance of side effects. Characterizing neuroplasticity in Parkinson’s disease and in response to the current treatments might provide the bases for the development of novel therapeutic strategies.

FOR SPECIALISTS

The team combines multilevel expertise and skills to study cellular interactions and neuroplasticity in the adult brain, in particular in the context of basal ganglia-related pathologies, using rodent models.

Ongoing projects are centered on the pathophysiology and treatment of Parkinson’s disease (PD) and the role of glutamatergic systems, with 4 research axes:

1. The anatomofunctional organization of the basal ganglia network and its remodeling in response to dopamine depletion in PD.

2. The cellular/molecular bases of the beneficial or side-effects of the current treatments for PD, i.e. deep brain stimulation of the subthalamic nucleus and L-DOPA treatment, and their interactions. Particular interest is given to activity-driven plasticity by deep brain stimulation at long-term (we own a patented microstimulator allowing chronic stimulation in behaving rat), in possible relationship with motor and non-motor PD symptoms.

3. The research and preclinical evaluation of new therapeutic strategies (novel anatomical targets for DBS and new pharmacological options targeting glutamate systems, such as metabotropic glutamate receptors).

4. The cell death mechanisms linked to dysfunction of glutamate transporters, with the hypothesis that they might contribute to the progression of PD’s neuropathological processes.

Lydia's lab perfom electrophysiology experiment to study neurodegenerescence and cell therapy in mus musculus

Optogenetic control of the activity of striatal cholinergic neurons : in vivo electrophysiological recording illustrating the inhibition of these interneurons by photostimulation of halorhodopsine.

Our approach combines the use or development of relevant experimental models in rodents (chronic deep brain stimulation, genetic model of cell specific ablation, optogenetic modulation of neuronal activity) with a variety of analytic tools including functional anatomy, electrophysiology (in vitro and in vivo), neurochemistry and molecular/cellular biology.

Main publications

PUBLICATION

September 26th, 2016

TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons.

Caubit X, Gubellini P, Andrieux J, Roubertoux PL, Metwaly M1, Jacq B, Fatmi A, Had-Aissouni L, Kwan KY, Salin P, Carlier M, Liedén A, Rudd E, Shinawi M, Vincent-Delorme C, Cuisset JM, Lemaitre MP10, Abderrehamane F, Duban B, Lemaitre JF, Woolf AS, Bockenhauer D, Severac D, Dubois E, Zhu Y, Sestan N, Garratt AN, Kerkerian-Le Goff L, Fasano L.

Nat Genet. 2016 Sep 26. PMID: 27668656

Cellular interactions, neurodegeneration and neuroplasticity

Group leader : L. Kerkerian – Le Goff

FOR BEGINNERS

FOR SPECIALISTS

Main publications

TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons.

Involvement of Striatal Cholinergic Interneurons and M1 and M4 Muscarinic Receptors in Motor Symptoms of Parkinson's Disease.

LAMP5 Fine-Tunes GABAergic Synaptic Transmission in Defined Circuits of the Mouse Brain.

Metabolic, synaptic and behavioral impact of 5-week chronic deep brain stimulation in hemiparkinsonian rats.

Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease.

Striatal Cholinergic Interneurons Control Motor Behavior and Basal Ganglia Function in Experimental Parkinsonism

Differential organization of cortical inputs to striatal projection neurons of the matrix compartment in rats.

Progressive brain metabolic changes under deep brain stimulation of subthalamic nucleus in parkinsonian rats.

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.

Oxygen glucose deprivation-induced astrocyte dysfunction provokes neuronal death through oxidative stress.

Cellular and Behavioral Outcomes of Dorsal Striatonigral Neuron Ablation: New Insights into Striatal Functions.

Distinct effects of mGlu4 receptor positive allosteric modulators at corticostriatal vs. striatopallidal synapses may differentially contribute to their antiparkinsonian action.

Progressive Parkinsonism by acute dysfunction of excitatory amino acid transporters in the rat

Striatal molecular signature of subchronic subthalamic nucleus high frequency stimulation in parkinsonian rat.

Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia.

The nucleus accumbens 5-HTR₄-CART pathway ties anorexia to hyperactivity.

The nucleus accumbens 5-HTR₄-CART pathway ties anorexia to hyperactivity.

Portable microstimulator for chronic deep brain stimulation in freely moving rats.

Antiparkinsonian action of a selective group III mGlu receptor agonist is associated with reversal of subthalamonigral overactivity.

High frequency stimulation of the subthalamic nucleus impacts adult neurogenesis in a rat model of Parkinson's disease.

The added value of rabies virus as a retrograde tracer when combined with dual anterograde tract-tracing.

Deep brain stimulation mechanisms: beyond the concept of local functional inhibition.

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.

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.

[Acetylcholinesterase inhibitors in Alzheimer's disease: further comments on their mechanisms of action and therapeutic consequences].

Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury.

Ciliary neurotrophic factor protects striatal neurons against excitotoxicity by enhancing glial glutamate uptake.

Downstream mechanisms triggered by mitochondrial dysfunction in the basal ganglia: from experimental models to neurodegenerative diseases.

Effects of GPi and STN inactivation on physiological, motor, cognitive and motivational processes in animal models of Parkinson's disease.

Rationale for targeting the thalamic centre-median parafascicular complex in the surgical treatment of Parkinson's disease.

Cocaine-induced stereotypy is linked to an imbalance between the medial prefrontal and sensorimotor circuits of the basal ganglia.

Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism.

Mechanisms contributing to the phase-dependent regulation of neurogenesis by the novel antidepressant, agomelatine, in the adult rat hippocampus.

Different functional basal ganglia subcircuits associated with anti-akinetic and dyskinesiogenic effects of antiparkinsonian therapies.

Deep brain stimulation in neurological diseases and experimental models: from molecule to complex behavior.

Changes to interneuron-driven striatal microcircuits in a rat model of Parkinson's disease.

Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson's disease treatment.

Role of glutamate transporters in corticostriatal synaptic transmission.

Impact of surgery targeting the caudal intralaminar thalamic nuclei on the pathophysiological functioning of basal ganglia in a rat model of Parkinson's disease.

Importance of circadian rhythmicity in the cholinergic treatment of Alzheimer's disease: focus on galantamine*.

High-resolution neuroanatomical tract-tracing for the analysis of striatal microcircuits.

Plasma membrane expression of the neuronal glutamate transporter EAAC1 is regulated by glial factors: evidence for different regulatory pathways associated with neuronal maturation.

Preferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunction.

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.

High-frequency stimulation of the subthalamic nucleus potentiates L-DOPA-induced neurochemical changes in the striatum in a rat model of Parkinson's disease.

Deficits of glutamate transmission in the striatum of experimental hemiballism.

Chronic high-frequency stimulation of the subthalamic nucleus and L-DOPA treatment in experimental parkinsonism: effects on motor behaviour and striatal glutamate transmission.

The neuronal excitatory amino acid transporter EAAC1/EAAT3: does it represent a major actor at the brain excitatory synapse?

Glutamate leakage from a compartmentalized intracellular metabolic pool and activation of the lipoxygenase pathway mediate oxidative astrocyte death by reversed glutamate transport.

Ciliary neurotrophic factor activates astrocytes, redistributes their glutamate transporters GLAST and GLT-1 to raft microdomains, and improves glutamate handling in vivo.

Transient hippocampal down-regulation of Kv1.1 subunit mRNA during associative learning in rats.

Enhanced delivery of gamma-secretase inhibitor DAPT into the brain via an ascorbic acid mediated strategy.

Glial soluble factors regulate the activity and expression of the neuronal glutamate transporter EAAC1: implication of cholesterol.

Metabotropic glutamate 5 receptor blockade alleviates akinesia by normalizing activity of selective basal-ganglia structures in parkinsonian rats.

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Members more

Lydia Kerkerian - Le Goff

Roxane Benoit

Corinne Beurrier

Emilie Dinh

Paolo Gubellini

Philippe Kachidian

Jean-pierre Kessler

Gwenaëlle Laverne

Sylviane Lortet

Nicolas Maurice

Christophe Melon

André Nieoullon