NeuroFrance: Equipe 3

19.05.2021, 15:15 – 16:30 : SYMPOSIUM

S08 – New insights into pathophysiology of Neurodevelopmental Disorders. / Nouvel éclairage sur la physiopathologie des Troubles du Neuro-Développement.
Supported by NeurATRIS

Laurie Galvan

S08.3 – Is the striatum the missing piece of Autism Spectrum Disorder puzzle? / Le Striatum: pièce manquante pour compléter le puzzle des troubles du spectre autistique?

ASD is a neurodevelopmental disorder that is highly investigated at the neurodevelopmental and juvenile stages. Even though it is essential to understand the implementation of the disease during the developmental period, it is crucial to remember that ASD is a non-lethal and thus lifelong disorder. ASD symptoms are broad, and their intensity varies depending on the patients. They can be grouped into two broad categories, such as “Persistent deficits in social communication and interaction” and “Restricted, repetitive patterns of behavior.” Interestingly, many ASD symptoms such as motor stereotypies, cognitive flexibility, and emotion management are linked with the basal ganglia network, especially the striatum. Initially described as a network responsible for motor control, the basal ganglia is now recognized to be involved in habit formation and emotional “balance.” Even though these functions are deeply affected in ASD, this network is understudied in this field. Synaptic dysfunctions have been demonstrated in striatal neurons in some ASD models. The goal of our project is to create a framework for further studies by providing insight into the state of GABAergic neurotransmission in the adult striatum to highlight ASD dysfunctions versus senescence.

19.05.2021, 14:00 – 15:00  P2 – Poster session 2

Decourt Mélina

P2.28 – Involvement of fronto-striatal plasticity in the development of impulse control disorder: in vivo electrophysiology study in an experimental rat model

Decourt M. (Poitiers Cedex 9, France)¹, Balado E. (Poitiers Cedex 9, France)¹, Francheteau M. (Poitiers Cedex 9, France)¹, Fernagut P.-O. (Poitiers Cedex 9, France)¹, Benoit-Marand M. (Poitiers Cedex 9, France)^{1 1}Laboratoire des Neurosciences Expérimentales et Clinique (LNEC), Bât. B36, Poitiers Cedex 9

France Parkinson’s disease (PD) is characterized by the degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons, leading to motor and cognitive symptoms. Pramipexole (PPX, D2/D3 dopaminergic agonist) is effective to treat motor symptoms but induces non-motor side effects called impulse control disorders (ICD). Unlike motor side effects, little is known about the mechanisms responsible ICD and clinical data indicate that frontostriatal connectivity is impaired in patients with ICD. We hypothesize that ICD induced by PPX are associated with changes in frontostriatal plasticity similar to the adaptations responsible for motor side effects. Here, we assessed the involvement of frontostriatal transmission in the pathophysiology of ICD in an experimental rat model of PD after chronic treatment with PPX. Dopaminergic degeneration was induced by bilateral injection of a viral vector expressing human mutated alpha-synuclein (AAV-2 hA53Tα-syn) in the SNc.
We developed an ICD animal model using the Post-Training Signal Attenuation test. Lesioned animals, with or without PPX treatment, displayed an altered attenuation behavior. However, during the extinction phase, where operant responses are no longer rewarded, only lesioned animals treated with PPX showed an extinction deficit characterized by an increase in operant responses. Following this behavioural characterization, electrophysiological recordings in the dorsomedial striatum (DMS) were performed in anesthetized rats while stimulating the orbito-frontal cortex (OFC). We evaluated DMS spike probability in response to the OFC stimulation before and during 45 minutes after a high frequency stimulation (HFS). Control animals displayed a long-term increase of spike probability (LTP) while the dopaminergic lesion resulted in a decreased spike probability response (LTD). This change in fronto-striatal plasticity induced by the dopaminergic lesion was not rescued by the PPX treatment and PPX itself was also able to prevent HFS-induced LTP in control rats.
Our results suggest that both nigral dopaminergic loss and PPX concur to alter fronstostriatal transmission, thereby precluding adequate information processing in associative basal ganglia loops as a gateway for the development of ICD.

20.05.2021, 14:00 – 15:00 P4 – Poster Session 4

Maisterrena Alexandre

P4.06 – Major motor and gait deficits with sexual dimorphism in a Shank3 mutant mouse model

Maisterrena A. (Poitiers, France)¹, Matas E. (Poitiers, France)¹, Thabault M. (Poitiers, France)¹, Balado E. (Poitiers, France)¹, Francheteau M. (Poitiers, France)¹, Balbous A. (Poitiers, France)¹, Galvan L. (Poitiers, France)¹, Jaber M. (Poitiers, France)^{1 1}LNEC – INSERM U1084 – Université de Poitiers, Poitiers, France

Background: Contrasting findings were reported in several animal models with a Shank3 mutation used to induce various autism spectrum disorder (ASD) symptoms. Here, we aimed at investigating behavioral, cellular, and molecular consequences of a C-terminal (frameshift in exon 21) deletion in Shank3 protein in mice, a mutation that is also found in clinical conditions and which results in loss of major isoforms of Shank3. A special focus was made on cerebellar related parameters.

Methods: All three genotypes were analysed [wild type (WT), heterozygote (Shank3+/ΔC) and homozygote (Shank3 ΔC/ΔC)] and males and females were separated into two distinct groups. Motor and social behavior, gait, Purkinje cells (PC) and glutamatergic protein levels were determined. Behavioral and cellular procedures used here were previously validated using two environmental animal models of ASD. ANOVA and post-hoc analysis were used for statistical analysis.

Results: Shank3 ΔC/ΔC mice showed significant impairments in social novelty preference, stereotyped behavior and gait. These were accompanied by a decreased number of PC in restricted cerebellar sub-regions and decreased cerebellar expression of mGluR5. Females Shank3 ΔC/ΔC were less affected by the mutation than males. Shank3+/ΔC mice showed impairments only in social novelty preference, grooming, and decreased mGluR5 expression and that were to a much lesser extent than in Shank3 ΔC/ΔC mice.

Limitations: As Shank3 mutation is a haploinsufficiency, it is of interest to emphasize that Shank3+/ΔC mice showed only mild to no deficiencies compared to Shank3 ΔC/ΔC.

Conclusions: Our findings indicate that several behavioral, cellular, and molecular parameters are affected in this animal model. The reported deficits are more pronounced in males than in females. Additionally, male Shank3 ΔC/ΔC mice show more pronounced alterations than Shank3+/ΔC. Together with our previous findings in two environmental animal models of ASD, our studies indicate that gait dysfunction constitutes a robust set of motor ASD symptoms that may be considered for implementation in clinical settings as an early and quantitative diagnosis criteria.

Keywords: Gait, Sociability, Motor coordination, Cerebellum, Crus I, Crus II, Purkinje cells, mGluR5