Le Syndrome de l'X Fragile (FXS) est la forme héréditaire majoritaire dedéficience intellectuelle et la cause monogénique de l'autisme. Le FXS est causé par unemutation du gène Fragile X Mental Retardation 1 (Fmr1), qui entraîne son inactivationet l'absence d’expression de la protéine codée: Fragile X Mental Retardation Protein(FMRP). FMRP est une protéine de liaison à l’ARN, impliquée dans la régulation de lasynthèse protéiques à la synapse. Un rôle central est attribué au sous-type 5 desrécepteurs métabotropiques au glutamate du groupe I (mGluR5) dans laphysiopathologie du FXS. En effet, une réponse exagérée suite à l'activation de mGluR5pourrait expliquer le dysfonctionnement synaptique dans ce syndrôme. Bien que denombreux travaux aient mis l'accent sur la dérégulation de la synthèse des protéinessynaptiques comme une conséquence de cette signalisation accrue du mGluR5, il y aaussi un équilibre altéré dans l'association de mGluR5 avec les différentes isoformes desprotéines Homer, partenaires de densité post-synaptique (PSD) du mGluR5. Bien qu'uneabondante littérature décrit l'association mGluR5/Homer, les conséquences de laperturbation de cette interaction dans le contexte du FXS sont peu connues. Parconséquent, l'objectif de ma thèse était d'étudier les conséquences de la perturbation del’interaction mGluR5/Homer au niveau des propriétés et des fonctions de mGluR5, tellesque l'expression durant le développement, l'expression de surface et le ciblageaxonal/dendritique, l’internalisation déclenchée par l'agoniste, les dynamiques desurface, et la modulation des courants NMDAR induite par mGluR5.Dans un premier temps, nous avons étudié l’expression de surface de mGluR5dans des neurones hippocampiques in vitro issus de souris sauvages et Fmr1 KO, par destechniques d’immunofluorescence et de biotinylation. Nous avons constaté que mGluR5est plus exprimé à la surface neuronale et est différemment distribué dans les dendrites etles axones des neurones Fmr1 KO. Puis, nous avons démontré que cette altérationd’expression et de ciblage est une conséquence directe de l’altération de l’interactionmGluR5/Homer. Nous avons aussi observé que mGluR5, indépendamment del’altération de l’interaction mGluR5/Homer, ne subit pas d’internalisation suite sonactivation soutenue par DHPG dans les neurones Fmr1 KO.Dans la seconde partie de mon étude, nous avons étudié les conséquences de laperturbation de l’interaction mGluR5/Homer dans les dynamiques de surface de mGluR5et par conséquent pour la fonction du NMDAR dans les neurones Fmr1 KO. Par destechniques d'imagerie et de pistage moléculaire, nous avons constaté que l’altération ducomplexe mGluR5/Homer augmente spécifiquement la diffusion latérale à la synapsedes neurones hippocampiques Fmr1 KO in vitro.La mobilité élevée du mGluR5 conduit à une probabilité accrue d'une interactionphysique transitoire avec NMDAR dans la PSD du Fmr1 KO.Cette interaction altère la modulation, induite par mGluR5, des courantsNMDAR. En effet, en utilisant des enregistrements en patch-clamp de neuronespyramidaux de CA1 sur tranches couplés à la stimulation des fibres collatérales deSchaffer, nous avons constaté que les courants excitateurs post-synaptiques induits parNMDAR (NMDAR-EPSCs) présentent des amplitudes plus faibles dans les neuronesFmr1 KO. De plus, l'expression post-synaptique de mGluR5, induite par la dépression àlong-terme de NMDAR-EPSCs est réduite dans les neurones Fmr1 KO. Finalement,nous avons démontré que ces défauts des courants NMDAR sont dépendants de laperturbation de l’interaction mGluR5/Homer et altèrent les dynamiques de mGluR5.Cette étude pourrait avoir des conséquences dans le traitement desdysfonctionnements synaptiques du mGluR5 dans le FXS, en ciblant l’interactionmGluR5/Homer, et offre de nouvelles suggestions pour corriger la signalisationdéfectueuse sous-jacente aux troubles du spectre autistique. / Fragile X Syndrome (FXS) is the most common inherited form of intellectualdisability and autism. FXS is caused by a mutation in the fragile X mental retardation 1(Fmr1) gene which leads to the lack of the encoded FMRP protein. FMRP is an RNAbinding protein involved in protein synthesis regulation at synapses. Many evidencessuggest a central role of the Group-I metabotropic glutamate receptor subtype 5(mGluR5) in the FXS pathophysiology. In particular, an exaggerated signaling responsefollowing mGluR5 activation may underlie synaptic dysfunction in this disorder.Although much work has focused on the dysregulation of synaptic protein synthesis as aconsequence of this enhanced mGluR5 signaling, it becomes clear that in FXS there isalso an altered balance of mGluR5 association with Homer scaffolding proteins, whichare postsynaptic density (PSD) partners of mGluR5. Although an extensive literaturedescribes the mGluR5/Homer association, very little is known about the consequences ofthe disruption of this interaction in the FXS context. Therefore, the goal of my thesis wasto study the consequences of mGluR5/Homer crosstalk disruption in the Fmr1 knockout(KO) mouse model of FXS in terms of properties and functions of mGluR5, such asexpression during development, surface expression and axonal/dendritic targeting,agonist-induced internalization, surface dynamics and mGluR5-mediated modulation ofNMDA receptor (NMDAR) currents.In a first set of experiments we investigated the mGluR5 surface expression incultured hippocampal neurons from WT and Fmr1 KO mice by usingimmunofluorescence techniques and biotinylation assay. We found that mGluR5 wasmore expressed on the neuronal surface and was differently distributed in dendrites andaxons of Fmr1 KO cultured neurons. We then hypothesized that these alterations were adirect consequence of the mGluR5/Homer crosstalk disruption. We demonstrated thatthe altered expression and targeting of mGluR5 were critically dependent onmGluR5/Homer crosstalk disruption. We also observed that mGluR5 did not undergointernalization upon sustained mGluR5 activation with DHPG in Fmr1 KO neurons.This latter phenotype, however, was not dependent on the disruption of themGluR5/Homer crosstalk. Altogether, these results demonstrate that mGluR5/Homercrosstalk disruption contributes to the pathophysiology of FXS altering expression andtargeting of mGluR5 on the surface of Fmr1 KO neurons.In the second part of my study we investigated the consequences of the disruptedmGluR5/Homer crosstalk for the mGluR5 surface dynamics, and consequently forNMDAR function in Fmr1 KO neurons. Using a combination of live-cell imaging andsingle-molecule tracking, we found that mGluR5/Homer crosstalk disruption specificallyincreased the mGluR5 lateral diffusion at the synapse of cultured Fmr1 KO hippocampalneurons. The higher mGluR5 mobility resulted in an increased probability of transientphysical interaction with NMDAR in the PSD of Fmr1 KO. This interaction altered themGluR5-mediated modulation of NMDAR currents as evidenced by the two followingchanges. First, using patch-clamp recordings from CA1 pyramidal neurons, we foundthat NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs) evoked bySchaffer collateral stimulation showed lower amplitudes in Fmr1 KO neurons. Second,the postsynaptic expression of mGluR5 mediated long term depression (LTD) ofNMDAR-EPSCs was reduced in Fmr1 KO neurons. Finally, we demonstrated that thesedefects in NMDA currents were strongly dependent on the mGluR5/Homer crosstalkdisruption and altered mGluR5 dynamics.Altogether, our results show that mGluR5/Homer disruption contributes to themGluR5 dysregulation in Fmr1 KO neurons. This study might have implication for thetreatment of mGluR5 synaptic dysfunctions in FXS by targeting mGluR5/Homerinteraction and provide new suggestions to correct the defective signaling underlyingcognitive impairment and autism.

As a highly versatile signal, Ca2+ operates over a wide temporal range to regulate many different cellular processes, impacting nearly every aspect of cellular life including excitability, exocytosis, motility, apoptosis, and transcription. While it has been well recognized that Ca2+ acts as both a second messenger to regulate cell-cell communication upon external stimuli and as a first messenger to integrate extracellular with intracellular signaling in various cell types. Molecular bases for such regulation and related human diseases are largely hampered by the challenges related to key membrane proteins. In the present study, we first investigated the regulatory role of intracellular Ca2+ ([Ca2+]i) on Connexin45 (Cx45) gap junction through a ubiquitous Ca2+ sensor protein-Calmodulin (CaM). Using bioluminescence resonance energy transfer assay, this study provides the first evidence of direct association of Cx45 and CaM in a Ca2+-dependent manner in cells. Complementary approaches including bioinformatics analysis and various biophysical methods identified a putative CaM-binding site in the intracellular loop of Cx45 with high Ca2+/CaM-binding affinity and Ca2+-dependent binding mode that is different from alpha family of connexins. To understand the role of extracellular calcium in regulation of gap junction hemichannels, we would like to prove a possible Ca2+-binding site predicted by our computational algorithm MUGSR in Connexin 26 (Cx26) through mutagenesis study, metal binding affinity measurement, conformational changes examination of purified Cx26 protein from Sf9; however, we failed to achieve this goal due to either the limitation of available methods or lethal effect of mutating the predicted Ca2+-binding ligand. Additionally, in this study, we identified a putative Ca2+-binding site in metabotropic glutamate receptor 5 (mGluR5) and demonstrated the importance of this Ca2+-binding site in activation of mGluR5 and modulating the actions of other orthosteric ligands on mGluR5. In addition, we successfully solved the first crystal structure of the extracellular domain of Ca2+-sensing receptor (CaSR) bound with Mg2+ and an unexpected Trp derivative. The extensive study of mechanism of CaSR function specifically through Mg2+-binding site and the unexpected ligand-binding site was done using several cell-based assays in wild type CaSR and mutants. Studies in this dissertation provides more information on how Ca2+ regulates gap junction channels, modulates mGluR5 activities and structural basis for regulation of CaSR by Mg2+ and an unexpected Trp derivative co-agonist.

Cortical malformations from altered development are common causes of human epilepsy. The cellular mechanisms responsible for the epileptic state of cortex remain unclear and a significant portion of these cases do not respond to treatment. Previous electrophysiological recordings in the Jacobs lab in a rat polymicrogyria model indicated an increased response to group I metabotropic glutamate receptor agonists in the region adjacent to the malformation (PMZ). In addition there was a novel response in low threshold spiking (LTS) interneurons via mGluR5 activation. To determine whether cell specific expression of these receptors was altered in malformed cortex immunohistochemical stains were performed for group I mGluRs along with non-overlapping interneuron subtype specific markers, a neuronal marker and general inhibitory cell marker. There was no altered mGluR5 expression seen in the PMZ. There was an altered expression seen in PMZ mGluR1α labeled cells and cells in other cortical regions.

Epilepsy has been previously attributed to either increased excitation or decreased inhibition. With this closed frame of mind, modern medicine has been unable to develop a permanent treatment against the mechanisms of epilepsy. In order to treat patients with intractable seizures, especially those caused by developmental malformations, it is essential to understand the entirety of mechanisms that could possibly play a role in the abnormal cortical function. One such developmental malformation is known as polymicrogyria. Epileptogenesis occurs in an area laterally adjacent to this malformation known as the paramicrogyral region (PMR). Past studies have narrowed down the potential cause of this increased network excitation to a certain type of inhibitory interneuron, the somatostatin (SS) interneuron. Additionally, previous studies have shown an increase in the mGlu5 receptor on this interneurons in the PMR region only and not in control tissue, meaning that targeting these receptors as treatment will not affect normal functioning tissue. These results lead to our hypothesis: blockade of the mGluRs will decrease the 2 activity of SS interneurons and thereby prevent the generation of epileptiform activity and increased SS output in malformed cortex. Utilizing the freeze-lesion model for microgyria in transgenic mice expressing Channelrhodopsin optogenetic channels in SS interneurons, we assessed the contribution of these SS interneurons in four different animal groups: control or PMR treated with either Gabapentin, a current AED (antiepileptic drug), or MTEP, an mGlu5 receptor antagonist. We tested the effects of these two drugs on SS interneuron output to determine whether they decrease the over activation in the PMR that has been previously studied. The following study revealed no correlation between Gabapentin-treated animals and a decrease in epileptiform activity. Additionally, no significant difference was seen between the MTEP-treated groups in the protocols that were measured.

Metabotropic glutamate receptor 5 (mGluR5) is a key regulator of numerous brain functions including memory, cognition, and motor behavior. Dysregulation of mGluR5 signaling is evident in Huntington's disease (HD) neuropathology, an inherited, neurodegenerative disease characterized with progressive deterioration in motor, cognitive, and psychiatric functions. In this context, two cellular proteins draw particular interest for this thesis: vesicular glutamate transporter 3 (VGLUT3) and optineurin (OPTN). VGLUT3 modulates glutamate release from selected neurons that are affected by HD, while OPTN is a mGluR5-interacting protein and contributes to neuronal vulnerability in HD. However, current evidence on their involvement in mGluR5 signaling and HD pathogenesis is still lacking. Using VGLUT3 knockout (VGLUT3⁻ᐟ⁻) mice, we showed that this transporter dynamically regulated glutamate receptor densities in different brain regions. Of note, VGLUT3 deletion upregulated mGluR5 in the cerebral cortex and the striatum, unlike the hippocampus which exhibited reduced mGluR5 cell surface densities. We then crossed VGLUT3⁻ᐟ⁻ mice with the zQ175 knock-in mouse model of HD (zQ175:VGLUT3⁻ᐟ⁻) to assess the impact of VGLUT3 transmission loss on HD progression. The longitudinal behavioral assessment revealed that VGLUT3 ablation rescued the deficits in motor coordination and short-term memory in both male and female zQ175 mice throughout 15 months of age. Furthermore, VGLUT3 deletion rescued striatal cell loss likely via activation of Akt and ERK1/2 cellular pathways, with no impact on total mutant huntingtin aggregation or the associated microgliosis. To delineate the role of OPTN in mGluR5 signaling, we employed a CRISPR/Cas9 OPTN-deficient cell line and global OPTN knockout mice. We demonstrated that OPTN was essential for mGluR5-mediated canonical signaling and ERK1/2 activation in both the striatal cell line, STHdh^Q7/Q7, and acute hippocampal slices. We then showed that OPTN deletion impaired autophagic machinery via GSK3β/ZBTB16 and mTOR/ULK1 signaling pathways downstream of mGluR5. This work offers novel insights into the molecular roles of VGLUT3 transmission and OPTN in mGluR5 signaling and provides a rationale for their targeting to therapeutically mitigate pathological mGluR5 signaling in HD.

Dans la maladie de Parkinson (MP), la perte progressive des neurones dopaminergiques (DA) touche principalement la substantia nigra pars compacta (SNc). Les symptômes moteurs sont classiquement gérés par une thérapie dopaminergique de remplacement (TDR). Conjointement à la levodopa, l’utilisation d’agonistes dopaminergiques permet de prévenir les complications motrices mais peut être associée à des troubles du système de récompense. Jusqu’à 14% des patients parkinsoniens sous TRD peuvent souffrir de comportement « addiction-like » tels que le pari pathologique, l’hypersexualité ou une prise compulsive de la médication DA. A ce jour la seule solution thérapeutique consiste à diminuer la TRD ce qui détériore les symptômes moteurs. Les neuroadaptations conduisant à ces troubles du système de récompense demeurent mal comprises. Nous proposons un travail dans lequel nous avons évalué les propriétés appétitives de l’agoniste D2/D3 pramipexole (ppx) après une exposition chronique à la L-dopa dans un modèle de rat parkinsonien alpha-synucléine. Dans une première étude, nous avons évalué l’effet d’une stimulation répétée des récepteurs DA sur la sensibilisation du système de récompense en contexte parkinsonien. Nos résultats montrent un effet récompensant du ppx après administrations chronique de L-dopa et perte DA nigrostriatal induite par surexpression de l’alpha-synucléine. Aucune modification transcriptionnelle n’a été observée pour les récepteurs DA. Cependant, nous avons identifié une association entre lésion/traitement pharmacologique et des changements transcriptionnels potentiellement liés à un contexte d’addiction aux psychostimulants. Cette étude fournit des preuves suggérant fortement la lésion parkinsonienne et la thérapie L-dopa comme des facteurs conjointement impliqués dans le remodelage cérébral sous-tendant une préférence de place conditionnée pour le ppx. Les données moléculaires et pharmacologiques générées ont suggéré un rôle clé de la voie glutamatergique dans cette réponse comportementale. Ce résultat est cohérent avec la littérature décrivant un déséquilibre glutamatergique striatal dans les contextes d’addiction aux psychostimulants et de complications motrices associées à la MP. Ainsi, nous avons conçu une deuxième étude visant à investiguer plus avant le potentiel thérapeutique d’une inhibition des récepteurs glutamatergiques. Une lésion bilatérale de la SNc a été réalisée par surexpression de la protéine alpha-synucléine au moyen d’un vecteur AAV. Suite à cette lésion, un traitement chronique à la L-dopa a été réalisé. L’effet de l’antagoniste des récepteurs mGluR5 (metabotropic glutamate receptor 5) MPEP sur les propriétés renforçatrices du ppx a été évalué dans un paradigme de préférence de place conditionnée. Enfin, une analyse des changements d’expression de protéines d’intérêt a été réalisé afin d’associer changements comportementaux drogue/lésion induits et paramètres moléculaires. L’acquisition et l’expression de la préférence de place ppx-induite a été abolie par le MPEP. De plus, nous avons identifié des réseaux neuraux et des modifications d’expression protéiques sous-tendant les plasticités striatales associées à la réponse comportementale. L’ensemble de ces travaux apporte de nouvelles idées sur le contexte physiopathologique associé aux troubles du système de récompense dans la MP. Des données moléculaires et pharmacologiques convergentes suggèrent fortement le mGluR5 comme une cible thérapeutique prometteuse. / In Parkinson’s Disease (PD), the progressive dopaminergic (DA) cell loss mainly affects the substantia nigra pars compacta (SNc). The motor symptoms are classically managed by DA replacement therapies (DRT). Although adding DA agonists to levodopa treatment may contribute to prevent motor complications, it may be associated with drug‑induced changes in reward related pathways. Up to 14% of PD patients under DRT may suffer from ‘addiction‑like’ behavior such as pathological gambling, hypersexuality or DA medication‑induced substance abuse. To date, the only therapeutic answer consists in lowering the DA medications which deteriorates the motor symptoms. Neuroadaptations leading to reward bias in PD patients under DRT are still poorly understood. To address this challenge, we propose a work in which we have assessed the rewarding effect of the D2/D3 agonist pramipexole (ppx) after chronic exposure to L‑dopa in an alpha-synuclein PD rat model. In a first study, we assessed the effect of repeated DA receptors stimulations on sensitization of the reward system in a parkinsonian context. Our findings demonstrated that ppx had a rewarding effect after chronic L-dopa administrations and alpha-synuclein-mediated nigral loss. No transcriptional changes within DA receptors were highlighted. However, we identified an association between the main drug or lesion and transcriptional changes which were potentially related to the context of psychostimulant addiction. This study provides evidences strongly suggesting that PD-like lesion and L-dopa therapy were concomitant factors involved in striatal remodeling underlying the ppx-induced place preference. Molecular and pharmacological data suggested a key involvement ofthe glutamatergic pathway in this behavioral outcome. These data were consistent with literature describing major striatal glutamate imbalance as a common feature of drug addiction and Parkinson’s disease physiopathological contexts. Hence, we designed a second study aiming to further investigate the therapeutic potential of glutamatergic receptors inhibition. A bilateral lesion of the SNc was performed in the rat using AAV-mediated overexpression of the alpha-synuclein. This lesion was followed by chronic L-dopa administrations. Then, the effect of the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP on ppx reinforcing properties was assessed in a place conditioning paradigm. Finally, analysis at the protein level was conducted to associate drug and lesion induced behavioral changes to molecular endpoints. Acquisition and expression of the ppx-induced place preference was abolished by the MPEP. Furthermore, we identified neural networks and protein changes underlying the striatal remodeling associated with the behavioral outcome. All this work provides new insights into the physiopathological context associated to the PD/DRT related reward bias. Convergent molecular and pharmacological data strongly suggest mGluR5 as a promising therapeutic target.

Doctor of Philosophy / Department of Psychology / Mary E. Cain / Glutamate contributes to the neurological and behavioral changes that occur during differential rearing, and those that occur during conditioned hyperactivity and sensitization. Metabotropic glutamate receptor 5 (mGluR5) in particular contributes to the psychostimulant reward pathway, plasticity, and differential rearing. The present study examined the role of mGluR5 in conditioning and sensitization in differentially reared rats. Rats were reared in an enriched (EC), impoverished (IC), or social (SC) condition for 30 days, after which they received repeated amphetamine (0.3 mg/kg) or saline injections. Following training, rats received an injection of the mGluR5 antagonist MTEP or saline prior to undergoing conditioned hyperactivity and sensitization tests. Results showed that MTEP attenuated conditioned hyperactivity and sensitization in IC but not EC and SC rats, suggesting that glutamatergic changes occur during differential rearing that alter the effects of MTEP on amphetamine conditioning and sensitization. Additionally, results demonstrated that enrichment rearing has a protective effect against conditioned hyperactivity at low doses of amphetamine.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

The ventral tegmental area (VTA) is an important component of the mesolimbic dopamine circuit and processes reward and motivational behaviors. In response to drug exposure, synaptic connections of this circuit can be rewired via synaptic plasticity—a phenomenon thought be responsible for the pathology of addiction. While much is known about dopamine neuron plasticity, less is known regarding plasticity exhibited by VTA GABA cells, specifically inhibitory inputs from outside the VTA. Expanding on the work of Bocklisch et al. (2013), we investigated the plasticity of inhibitory inputs to VTA GABA neurons. Using whole cell electrophysiology in GAD67 GFP mice, we observed that these VTA GABA cells can experience either long-term potentiation (LTP) or long-term depression (LTD) in response to a 5 Hz stimulus. While neither the LTP nor LTD appear to be mediated by the cannabinoid-1 receptor (CB1), the nitric oxide synthase (NOS) pathway, or the dopamine-2 (D2) receptor, the LTP is blocked by APV, an NMDA receptor antagonist, and the LTD is blocked by CGP 54626, an antagonist of the GABAB receptor. Additionally, µ-opioid and adenosine-1 receptors modulated plasticity at this synapse, but chronic morphine administration (10mg/kg) did not block the observed LTP or LTD. Furthermore, we used an optogenetic approach in VGAT-Cre mice to target inhibitory inputs from the lateral hypothalamus (LH) to the VTA. An optical stimulus (5 Hz) caused these inputs to depress, which has not been previously described and may be behaviorally important in reward processing. These novel findings increase our understanding of VTA neural circuitry, ultimately increasing our capacity to better comprehend and treat the pathology of addiction. Additionally, changes in synaptic strength in hippocampal CA1 pyramidal cells are thought to be responsible for the acquisition and retention of short-term memory. Feedforward stratum radiatum interneurons of many subtypes experience LTD, short-term depression (STD), or lack of plasticity, but it is not known whether plasticity correlates with specific interneuron subtypes. Using whole cell electrophysiology and qPCR, we characterized the plasticity expressed by hippocampal interneurons in correlation with their mRNA expression patterns to determine cell subtype. We also assessed the expression of endocannabinoid (eCB) biosynthetic enzymes as well as metabotropic glutamate receptor subunits known to mediate plasticity. Cells exhibiting LTD tended to express mRNA for at least one of the eCB biosynthetic enzymes and the metabotropic glutamate receptor subunit mGluR5. mGluR5 was not expressed by cells exhibiting STD or no plasticity. Cells that exhibited short-term depression tended to express mRNA for at least one of the eCB biosynthetic enzymes, but not mGluR5. This suggests that stratum radiatum interneuron plasticity can be predicted based on mGluR expression, and that these different types of plasticity may have some importance in hippocampal function.

Yes / A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APPswe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling. / Wellcome Trust, Grant/Award Number: 200646/Z/16/Z