As células T exercem papel crucial nas respostas imunes adaptativas e em doenças autoimunes, como a esclerose múltipla. O glutamato, neurotransmissor mais abundante no SNC, age por meio de duas famílias de receptores: metabotrópico e ionotrópico. As células T são alvo do glutamato durante a ativação e apresentação de antígenos, pois está presente nas sinapses imunológicas, porém, pouco se sabe a respeito de seu papel na função das células T. Nós estudamos o papel do NMDAR nas respostas mediadas por células T. In vitro, o uso do antagonista MK801 reduziu a linfoproliferação e a síntese de IFN-γ e IL-17A, bem com o NMDA reduziu a proliferação e produção de IFN-γ e IL-17A. In vivo, o MK801 reduziu a gravidade da EAE, resultado da menor infiltração de linfócitos Th1 e Th17 no SNC. Além disso, o MK801 reduziu a expressão de Rorc, Il17a, Stat4, Ccr4, Ccr6 e Ifna2 no SNC. Em suma, esses dados confirmam que o NMDAR exerce papel nas funções mediadas por células T, indicando que as células T são alvos do excesso do glutamato via NMDAR em doenças neuroinflamatórias. / T cells play a crucial role in adaptive immune responses and autoimmune diseases, such as multiple sclerosis. Glutamate is the most abundant neurotransmitter in the CNS, and it acts through two receptor families: metabotropic and ionotropic. T cells are target of glutamate during activation and antigen presentation, because glutamate is also present in the immunological synapses, however, little is known about its role on T cell functions. We investigated the role of NMDAR in immune-mediated T cell responses. In vitro, the use of the antagonist MK801 reduced T cell proliferation and cytokine production (IFN-γ e IL-17A), as well as NMDA reduced lymphocyte proliferation and IFN-γ e IL-17A production, in a dose dependent manner. In vivo, MK801 diminished severity of EAE, result of the minor Th1 and Th17 infiltration in the CNS. In addition, MK801 reduced Rorc, Il17a, Stat4, Ccr4, Ccr6 and Ifna2 expression in the CNS. In short, our data confirm that the NMDAR play a role in T cell-mediated functions, indicating that T cells are target of glutamate excess via NMDAR in neuroinflammatory diseases.

As células T exercem papel crucial nas respostas imunes adaptativas e em doenças autoimunes, como a esclerose múltipla. O glutamato, neurotransmissor mais abundante no SNC, age por meio de duas famílias de receptores: metabotrópico e ionotrópico. As células T são alvo do glutamato durante a ativação e apresentação de antígenos, pois está presente nas sinapses imunológicas, porém, pouco se sabe a respeito de seu papel na função das células T. Nós estudamos o papel do NMDAR nas respostas mediadas por células T. In vitro, o uso do antagonista MK801 reduziu a linfoproliferação e a síntese de IFN-γ e IL-17A, bem com o NMDA reduziu a proliferação e produção de IFN-γ e IL-17A. In vivo, o MK801 reduziu a gravidade da EAE, resultado da menor infiltração de linfócitos Th1 e Th17 no SNC. Além disso, o MK801 reduziu a expressão de Rorc, Il17a, Stat4, Ccr4, Ccr6 e Ifna2 no SNC. Em suma, esses dados confirmam que o NMDAR exerce papel nas funções mediadas por células T, indicando que as células T são alvos do excesso do glutamato via NMDAR em doenças neuroinflamatórias. / T cells play a crucial role in adaptive immune responses and autoimmune diseases, such as multiple sclerosis. Glutamate is the most abundant neurotransmitter in the CNS, and it acts through two receptor families: metabotropic and ionotropic. T cells are target of glutamate during activation and antigen presentation, because glutamate is also present in the immunological synapses, however, little is known about its role on T cell functions. We investigated the role of NMDAR in immune-mediated T cell responses. In vitro, the use of the antagonist MK801 reduced T cell proliferation and cytokine production (IFN-γ e IL-17A), as well as NMDA reduced lymphocyte proliferation and IFN-γ e IL-17A production, in a dose dependent manner. In vivo, MK801 diminished severity of EAE, result of the minor Th1 and Th17 infiltration in the CNS. In addition, MK801 reduced Rorc, Il17a, Stat4, Ccr4, Ccr6 and Ifna2 expression in the CNS. In short, our data confirm that the NMDAR play a role in T cell-mediated functions, indicating that T cells are target of glutamate excess via NMDAR in neuroinflammatory diseases.

Parkinson’s Disease affects 10 million people worldwide, with 40% of patients developing an associated psychosis which has been identified by studies as the number one source of caretaker distress and is related to increased mortality. This is further complicated by the fact that typical antipsychotic drugs worsen many of the motor symptoms implicated in Parkinson’s Disease, with only one commercially available drug able to ameliorate both symptoms. This problem ushers the development of novel drugs to treat these symptoms, as first tested on research animals. Complicating matters, drug effectiveness on the degree of psychosis is hard to obtain in animals without a reliable biomarker. However, a hallmark of psychotic states is thought to be the reduced coordination between brain structures, through neuronal synchronization, as demonstrated by steady-state responses and is suggested to be a potential biomarker of psychosis. By building a MATLAB software we were able to analyze the degree of neural synchronization between structures, during an auditory steady-state response, in rats that had been unilaterally lesioned by the 6-Hydroxydopamine model of Parkinson’s Disease, before and after administration of the psychotomimetic drug MK801. These rats had been chronically implanted with 128-channel multi electrode array, enabling us to measure the strength of coherence between several limbic structures, associated with auditory processing, from the sampled local field potential, identifying the degree of synchronization in the animal brain. As our data demonstrate that coherence levels dropped in the psychotic drug state, for structures in both the healthy and the Parkinsonian hemisphere, we are able to further demonstrate the validity of coherence measures as a biomarker for psychosis. These results demonstrate that our software can be used as a tool to assess the therapeutic response of drugs developed, aimed at treating Parkinson’s associated psychosis. / Parkinsons sjukdom drabbar 10 miljoner världen över, där 40% av patienterna utvecklar en associerad psykos vilket har visats vara en av de största stressfaktorerna för deras vårdgivare och är även förknippat med en högre dödlighetsgrad. Denna situation förvärras av det faktum att de vanliga antipsykotiska drogerna kan förvärra många av de motoriska symptom som utgörs av Parkinsons sjukdom och det finns i dagsläget enbart en enda kommersiell drog som kan dämpa bägge symptom samtidigt. Detta problem frammanar vidare utveckling av nya läkemedel som kan behandla dessa symptom, som innebär att de först måste testas på försöksdjur. En komplikation som uppstår i relation till detta är svårigheten att utvärdera om läkemedel har någon terapeutisk effekt på de psykotiska tillstånden, enbart genom att observera försöksdjurens beteenden, och en pålitlig biomarkör krävs istället. En lösning kan dock finnas i det faktum att psykotiska tillstånd karaktäriseras av en reducerad förmåga för olika hjärnområden att koordinera genom neural synkronisering vilket demonstreras av ‘steady- state’ responser. Detta föreslår att ett mått på graden av koordineringsförmåga kan agera som en möjlig biomarkör för psykotiska tillstånd. Genom att konstruera ett MATLAB-program kunde vi analysera graden av synkronicitet mellan hjärnstrukturer, under den auditiva steady- state responsen i råttor som hade blivit ensidigt lesionerade genom 6-Hydroxiddopamin modellen av Parkinsons sjukdom, före och efter administration av den psykotomimetiska drogen MK801. Dessa råttor hade blivit kroniskt implanterade med 128 elektroder vilket möjliggjorde att vi kunde mäta styrkan i koherens i den lokala fält potentialen mellan limbiska strukturer, som är associerade med auditiv processering, vilket möjliggjorde identifiering av3dessa strukturers synkronicitet. Vår data demonstrerar att koherensen minskade under det psykotiska drogtillståndet för limbiska strukturer både i den intakta och den lesionerade hjärnhalvan. Detta är en vidare demonstration av att koherensnivåer kan agera som en biomarkör för det psykotiska tillståndet, liksom att vår mjukvara kan nyttjas som ett verktyg för att utvärdera nya läkemedels behandlingsförmåga på Parkinsons psykos.

Der wichtigste exzitatorische Neurotransmitter Glutamat spielt eine grosse Rolle in der Gehirnentwicklung, wie neuronale Migration und Synaptogenese. Ob glutamaterge Stimulation für das Überleben entwickelnder Neuronen notwendig ist, war bislang jedoch unbekannt. Um zu untersuchen, ob eine Hemmung von Glutamatrezeptoren im unreifen Gehirn zu Neurodegeneration führt, wurden Ratten im Alter von 1 bis 31 Tagen für 24 Stunden mit dem N-Methyl-D-Aspartat-(NMDA) Glutamatrezeptorantagonisten Dizocilpin (MK801) behandelt. Die Dichte neuronaler Degeneration wurde mikroskopisch in Kupfer-Silber- und TUNEL- gefärbten Hirnschnittpräparaten ermittelt und Unterschiede mittels ANOVA analysiert (Signifikanzniveau p / The predominant excitatory neurotransmitter glutamate plays a major role in certain aspects of neural development. However, whether developing neurons depend on glutamate for survival remains unknown. To investigate if deprivation of glutamate stimulation in the immature mammalian brain causes neuronal cell death (apoptosis), rat pups aged 0 to 30 days were treated for 24 hours with dizocilpine maleate (MK801), an N-methyl-D-aspartate-(NMDA) glutamate receptor antagonist. Density of neural degeneration was evaluated by a stereological dissector method in cupric-silver and TUNEL-stained brain slices. Groups were compared by ANOVA and significance considered at p