The somatosensory corticothalamic (CT) circuit processes ascending sensory signals, and disruption to the balance of excitation and inhibition (E/I) within CT circuitry leads to absence seizures, sleep disorders, and attention deficits. E/I balance may be restored by independently modulating excitatory CT input to the ventral posteromedial (VPM) thalamus and inhibitory input to the VPM through the CT-thalamic reticular nucleus (nRT)-VPM pathway. This work revealed novel N-methyl-D-aspartate receptor (NMDAR) nucleus-specific and frequency-dependent functional diversity in the somatosensory CT circuit. Specifically, these findings illustrate the different effects of NMDAR negative modulation in the nRT and the VPM, which offers a method to preferentially decrease high frequency excitatory CT input to the VPM while having no significant effect on nRT activity. These results demonstrate the potential of utilizing NMDAR selective modulators to decrease overall excitation within the somatosensory CT circuit. Further investigation is required to elucidate the precise mechanisms underlying this phenomenon, including where NMDARs are localized at CT synapses and the effect of positive NMDAR modulators on nRT and VPM activity. / Master of Science / The sensory gating mechanism helps our brain to select essential sensory information to process. Impairment of this sensory gating has been reported in epilepsy, schizophrenia, and autism. The somatosensory corticothalamic (CT) circuit oversea the sensory gating process by adjusting how much excitation and inhibition signals are integrated into the thalamus. Disruption of the balance of excitation and inhibition (E/I) within CT circuitry leads to the absence seizures, sleep disorders, and attention deficits. Our work revealed one of the glutamate receptors N-methyl-D-aspartate receptor (NMDAR), has nucleus-specific and frequency-dependent functional diversity in the somatosensory CT circuit. By targeting the different NMDAR subunits in the circuit, we were able to preferentially decrease high-frequency excitatory input to the thalamus while having no significant effect on inhibitory input. These results offer the potential to utilize NMDAR selective modulators to decrease overall excitation within the somatosensory CT circuit, which is useful to restore the disrupted E/I balance in the thalamus from a variety of neurological diseases. Further investigation is required to elucidate the precise mechanisms underlying this phenomenon.

Doctoral thesis assessing the effects of one-week of escitalopram administration on healthy humans during sequence motor learning training. Published in 3 research articles.

In this work, we propose an approach that allows to explore the potential pathophysiological mechanisms (at neuronal population level) of ictogenesis by combining clinical intracranial electroencephalographic (iEEG) recordings with a neural mass model. IEEG recordings from temporal lobe epilepsy (TLE) patients around seizure onset were investigated. Physiologically meaningful parameters (average synaptic gains of the excitatory, slow and fast inhibitory population, Ae, B and G) were identified during interictal to ictal transition. We analyzed the temporal evolution of four ratios, i.e. Ae/G, Ae/B, Ae/(B + G), and B/G. The excitation/inhibition ratio increased around seizure onset and decreased before seizure offset, suggesting the disturbance and restoration of balance between excitation and inhibition around seizure onset and before seizure offset, respectively. Moreover, the slow inhibition may have an earlier effect on the breakdown of excitation/inhibition balance. Results confirm the decrease in excitation/inhibition ratio upon seizure termination in human temporal lobe epilepsy, as revealed by optogenetic approaches both in vivo in animal models and in vitro. We further explored the distribution of the average synaptic gains in parameter space and their temporal evolution, i.e. the path through the model parameter space, in TLE patients. Results showed that the synaptic gain values located roughly on a plane before seizure onset, dispersed during ictal and returned when the seizure terminated. Cluster analysis was performed on seizure paths and demonstrated consistency in synaptic gain evolution across different seizures from individual patients. Furthermore, two patient groups were identified, each one corresponding to a specific synaptic gain evolution in the parameter space during a seizure. Results were validated by a bootstrapping approach based on comparison with random paths. The differences in the path revealed variations in EEG dynamics for patients despite showing an identical seizure onset pattern. Our approach may have the potential to classify the epileptic patients into subgroups based on different mechanisms revealed by subtle changes in synaptic gains and further enable more robust decisions regarding treatment strategy. The increase of excitation/inhibition ratios, i.e. Ae/G, Ae/B and Ae/(B+G), around seizure onset makes them potential cues for seizure detection. We explored the feasibility of a model based seizure detection algorithm. A simple thresholding method was employed. We evaluated the algorithm against the manual scoring of a human expert on iEEG samples from patients suffering from different types of epilepsy. Results suggest that Ae/(B+G), i.e. excitation/(slow + fast inhibition) ratio, allowed the best performance and that the algorithm best suited TLE patients. Leave-one-out cross-validation showed that the algorithm achieved 94.74% sensitivity for TLE patients. The median false positive rate was 0.16 per hour, and median detection delay was -1.0 s. Of interest, the values of the threshold determined by leave-one-out cross-validation for TLE patients were quite constant, suggesting a general excitation/inhibition balance baseline in background iEEG among TLE patients. Such a model-based seizure detection approach is of clinical interest and could also achieve good performance for other types of epilepsy provided that more appropriate model, i.e. better describe epileptic EEG waveforms for other types of epilepsy, is implemented. Altogether, this thesis contributes to the field of epilepsy research from two perspectives. Scientifically, it gives new insights into the mechanisms underlying interictal to ictal transition, and facilitates better understanding of epileptic seizures. Clinically, it provides a tool for reviewing EEG data in a more efficient and objective manner and offers an opportunity for on-demand therapeutic devices. / Doctorat en Sciences de l'ingénieur et technologie / info:eu-repo/semantics/nonPublished

La déficience intellectuelle affecte de 1 à 3% de la population mondiale, ce qui en fait le trouble cognitif le plus commun de l’enfance. Notre groupe à découvert que des mutations dans le gène SYNGAP1 sont une cause fréquente de déficience intellectuelle non-syndromique, qui compte pour 1-3% de l’ensemble des cas. À titre d’exemple, le syndrome du X fragile, qui est la cause monogénique la plus fréquente de déficience intellectuelle, compte pour environ 2% des cas. Plusieurs patients affectés au niveau de SYNGAP1 présentent également des symptômes de l’autisme et d’une forme d’épilepsie. Notre groupe a également montré que SYNGAP1 cause la déficience intellectuelle par un mécanisme d’haploinsuffisance. SYNGAP1 code pour une protéine exprimée exclusivement dans le cerveau qui interagit avec la sous-unité GluN2B des récepteurs glutamatergique de type NMDA (NMDAR). SYNGAP1 possède une activité activatrice de Ras-GTPase qui régule négativement Ras au niveau des synapses excitatrices. Les souris hétérozygotes pour Syngap1 (souris Syngap1+/-) présentent des anomalies de comportement et des déficits cognitifs, ce qui en fait un bon modèle d’étude. Plusieurs études rapportent que l’haploinsuffisance de Syngap1 affecte le développement cérébral en perturbant l’activité et la plasticité des neurones excitateurs. Le déséquilibre excitation/inhibition est une théorie émergente de l’origine de la déficience intellectuelle et de l’autisme. Cependant, plusieurs groupes y compris le nôtre ont rapporté que Syngap1 est également exprimé dans au moins une sous-population d’interneurones GABAergiques. Notre hypothèse était donc que l’haploinsuffisance de Syngap1 dans les interneurones contribuerait en partie aux déficits cognitifs et au déséquilibre d’excitation/inhibition observés chez les souris Syngap1+/-. Pour tester cette hypothèse, nous avons généré un modèle de souris transgéniques dont l’expression de Syngap1 a été diminuée uniquement dans les interneurones dérivés des éminences ganglionnaires médianes qui expriment le facteur de transcription Nkx2.1 (souris Tg(Nkx2,1-Cre);Syngap1). Nous avons observé une diminution des courants postsynaptiques inhibiteurs miniatures (mIPSCs) au niveau des cellules pyramidales des couches 2/3 du cortex somatosensoriel primaire (S1) et dans le CA1 de l’hippocampe des souris Tg(Nkx2,1-Cre);Syngap1. Ces résultats supportent donc l’hypothèse selon laquelle la perte de Syngap1 dans les interneurones contribue au déséquilibre d’excitation/inhibition. De manière intéressante, nous avons également observé que les courants postsynaptiques excitateurs miniatures (mEPSCs) étaient augmentés dans le cortex S1, mais diminués dans le CA1 de l’hippocampe. Par la suite, nous avons testé si les mécanismes de plasticité synaptique qui sous-tendraient l’apprentissage étaient affectés par l’haploinsuffisance de Syngap1 dans les interneurones. Nous avons pu montrer que la potentialisation à long terme (LTP) NMDAR-dépendante était diminuée chez les souris Tg(Nkx2,1-Cre);Syngap1, sans que la dépression à long terme (LTD) NMDAR-dépendante soit affectée. Nous avons également montré que l’application d’un bloqueur des récepteurs GABAA renversait en partie le déficit de LTP rapporté chez les souris Syngap1+/-, suggérant qu’un déficit de désinhibition serait présent chez ces souris. L’ensemble de ces résultats supporte un rôle de Syngap1 dans les interneurones qui contribue aux déficits observés chez les souris affectées par l’haploinsuffisance de Syngap1. / Intellectual disability affects 1-3% of the world population, which make it the most common cognitive disorder of childhood. Our group discovered that mutation in the SYNGAP1 gene was a frequent cause of non-syndromic intellectual disability, accounting for 1-3% of the cases. For example, the fragile X syndrome, which is the most common monogenic cause of intellectual disability, accounts for 2% of all cases. Some patients affected by SYNGAP1 also showed autism spectrum disorder and epileptic seizures. Our group also showed that mutations in SYNGAP1 caused intellectual disability by an haploinsufficiency mechanism. SYNGAP1 codes for a protein expressed only in the brain which interacts with the GluN2B subunit of NMDA glutamatergic receptors (NMDAR). SYNGAP1 possesses a Ras-GAP activating activity which negatively regulates Ras at excitatory synapses. Heterozygote mice for Syngap1 (Syngap1+/- mice) show behaviour abnormalities and learning deficits, which makes them a good model of intellectual disability. Some studies showed that Syngap1 affects the brain development by perturbing the activity and plasticity of excitatory neurons. The excitatory/inhibitory imbalance is an emerging theory of the origin of intellectual disability and autism. However, some groups including ours, showed that Syngap1 is expressed in at least a subpopulation of GABAergic interneurons. Therefore, our hypothesis was that Syngap1 happloinsufficiency in interneurons contributes in part to the cognitive deficits and excitation/inhibition imbalance observed in Syngap1+/- mice. To test this hypothesis, we generated a transgenic mouse model where Syngap1 expression was decreased only in GABAergic interneurons derived from the medial ganglionic eminence, which expresses the transcription factor Nkx2.1 (Tg(Nkx2,1-Cre);Syngap1 mouse). We showed that miniature inhibitory postsynaptic currents (mIPSCs) were decreased in pyramidal cells in layers 2/3 in primary somatosensory cortex (S1) and in CA1 region of the hippocampus of Tg(Nkx2,1-Cre);Syngap1 mice. Those results suggest that Syngap1 haploinsufficiency in GABAergic interneurons contributes in part to the excitation/inhibition imbalance observed in Syngap1+/- mice. Interestingly, we also observed that miniature excitatory postsynaptic currents (mEPSCs) were increased in cortex S1 but decreased in CA1 region of the hippocampus. We further tested whether synaptic plasticity mechanisms that are thought to underlie learning and memory were affected by Syngap1 haploinsufficiency in GABAergic interneurons. We showed that NMDAR-dependent long-term potentiation (LTP) but not NMDAR-dependent long-term depression (LTD) was decreased in Tg(Nkx2,1-Cre);Syngap1 mice. We also showed that GABAA receptor blockade rescued in part the LTP deficit in Syngap1+/- mice, suggesting that a disinhibition deficit is present in these mice. Altogether, the results support a functional role of Syngap1 in GABAergic interneurons, which may in turn contributes to the deficit observed in Syngap1+/- mice.

Le cortex est une structure qui supporte de nombreux processus tels que perception sensorielle, processus cognitifs et mémorisation. Il fonctionne grâce à une association de neurones excitateurs (E) et inhibiteurs (I) interconnectés de façon récurrente par des synapses dynamiques qui ciblent les neurones pyramidaux de couche 5 (NPy5) élaborant les signaux de sortie du cortex. Cette organisation neuronale est régulée par un équilibre entre E et I. La dérégulation des réseaux neuronaux peut conduire à des pathologies telles que la dépression ou la schizophrénie. Le fonctionnement du cortex est modulé entre autres par la sérotonine, la dopamine, la D-sérine et la glycine. Ce travail de thèse porte sur l’effet des interactions entre neuromodulateurs via les récepteurs 5-HT1A, D1, D2, NMDA et GlyR sur la balance et la plasticité synaptique de E et I dans le cortex. Mes données électrophysiologiques montrent que l’interaction entre les récepteurs 5-HT1A et D1 limite l’induction de la LTD, tandis que l’interaction entre les récepteurs 5-HT1A et D2, grâce à un carrefour commun de signalisation GSK3β, favorise l’induction de la LTD. Je montre dans le cortex visuel de rat que la D-sérine est nécessaire à l’induction de la LTP et que les GlyR ont un rôle de « shunt » le long de la dendrite des NPy5, ce qui entraîne un basculement d’une LTP en « LTD-like » apparente. / The cortex is crucial for processes such as sensory perception, cognition and memory. Cortical organization is based on neuronal networks composed of excitatory (E) and inhibitory (I) neurons which target layer 5 pyramidal neurons. Dysfunctions of such networks result in psychiatric pathologies including major depression and schizophrenia. Regulations of cortical activity also involve neuromodulators such as serotonin, dopamine, D-serine and glycine. The current body of work decipher the interactions of the effects of 5-HT1A-, D1-, D2-, NMDA- and Glycine-receptors activation on the E-I balance and synaptic plasticity. The electrophysiological data that I have generated in the prefrontal cortex show that concomitant activation of 5-HT1A- and D1-receptors downregulates the induction of LTD whilst 5-HT1A coupled to D2-receptors activation promotes LTD induction, via a common modulation of GSK3β. I also collected data from the visual cortex, showing that D-serine is the co-agonist NMDA-receptor in this brain region and is, as such, required for LTP-induction. Glycine was instead found to act on dendritic Glycine-receptors, resulting in a shunt, which altered dendritic integration and thus turned LTP to a LTD-like effect at the somatic level.

La décharge des cellules de Purkinje (CP), neurone de sortie du cortex cérébelleux, joue un rôle majeur dans le contrôle moteur. Les CP reçoivent des entrées excitatrices provenant des cellules des grains (CG), lesquelles génèrent également une inhibition antérograde sur les CP via l’activation d’interneurones de la couche moléculaire (IN). Lors de ma thèse, j’ai étudié l’influence simultanée de la balance excitation-inhibition (E/I) et des plasticités à court terme aux synapses CG-IN-CP sur la décharge des CP, par des techniques d’électrophysiologie, d’optogénétique et de simulation. Ces travaux démontrent l’existence d’une hétérogénéité d’E/I dans le cortex cérébelleux ainsi qu’une grande diversité de modulation des CP en réponse à la stimulation de CG. Le nombre de stimulation des CG influence fortement la direction et l’intensité de la modulation observée. Enfin, la combinaison de plasticités à court terme et d’E/I génère dans la décharge des CP des motifs de réponses complexes mais reproductibles, ayant sans doute un rôle essentiel dans l’encodage sensoriel. / Rate and temporal coding in Purkinje cells (PC), the sole output of the cerebellar cortex, play a major role in motor control. PC receives excitatory inputs from granule cells (GC) which also provide feedforward inhibition on PC through the activation of molecular layer interneurons (MLI). In this thesis, I studied the influence of the combined action of excitation/inhibition (E/I) balance and short-term plasticity of GC-MLI-PC synapses on PC discharge, by using electrophysiological recordings, optogenetic stimulation and modelling. This work demonstrates that E/I balances are not equalized in the cerebellar cortex and showed a wide distribution of PC discharge modulation in response to GC inputs, from an increase to a shut down of the discharge. The number of stims in GC bursts strongly controls the strength and sign of PC modulation. Lastly, the interplay between short-term plasticity and E/I balance implements complex but reproducible output patterns of PC responses to GC inputs that should play a key role in stimulus encoding by the cerebellar cortex.