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Striatal activity and synaptic features underlying dystonic muscle contraction
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Resumo: A distonia é uma doença do movimento caracterizada por contrações
musculares involuntárias e intermitentes, que levam a movimentos e
posturas anormais. A distonia DYT1 é a forma hereditária mais comum e é
causada por uma mutação no gene TOR1A. Apesar da sua causa genética bem
definida, a distonia DYT1 apresenta uma baixa penetrância (~30%). Como
resultado, surgiu o conceito de "second hit", sugerindo que fatores ambientais
adicionais podem ser necessários para desencadear a manifestação da
distonia. Embora tenham sido feitos progressos significativos na
compreensão da distonia, a sua fisiopatologia exata ainda não está clara. Os
gânglios da base, particularmente o estriado, desempenham um papel
fundamental no controlo dos movimentos voluntários. Supõe-se que um
desequilíbrio entre as vias direta e indireta possa levar às contrações
musculares anormais. No entanto, os mecanismos subjacentes não são bem
compreendidos. Alterações na plasticidade sináptica estriatal e na
complexidade dendrítica dos MSNs foram relatadas em modelos animais de
dystonia. No entanto, nenhum estudo examinou diferenças específicas entre
as vias. Este projeto tem como objetivo determinar a plasticidade estrutural
estriatal num modelo de ratinho de distonia DYT1, antes e 12 semanas após
um "second hit" (compressão do nervo ciático) conhecido por induzir
movimentos semelhantes à distonia. Utilizando imagens confocais de alta
resolução, analisámos a morfologia dendrítica das D1-MSNs marcados com
EYFP, por injeção retro-orbital de AAV9.Ef1.DIO.EYFP em ratinhos D1-Cre
cruzados com ratinhos DYT1 e com os respectivos controlos (WT). As
reconstruções 3D das imagens confocais dos D1-MSNs permitiram a
quantificação detalhada dos parâmetros dendríticos, nomeadamente análise
3D de Sholl, o comprimento total das dendrites, o número de dendrites, os
pontos de ramificação, a retilineidade e o volume do soma. Os nossos
resultados mostram que, embora o efeito da mutação DYT1 na complexidade
dendrítica não tenha atingido significância estatística, houve um aumento do
volume do soma nos ratinhos DYT1 em comparação com os controlos WT, 12
semanas após a compressão do nervo ciático. Estes resultados sugerem que
a disfunção da torsinaA, em combinação com um “second hit”, afeta a
plasticidade estrutural das D1-MSNs. O nosso estudo fornece novas informações sobre as anomalias morfológicas nas D1-MSNs associadas à distonia DYT1.
Abstract: Dystonia is a movement disorder characterized by involuntary and intermittent muscle contractions, leading to abnormal movements and postures. DYT-TOR1a dystonia (DYT1) is the most common hereditary form and it is caused by a mutation in the TOR1A gene. Despite its well-defined genetic cause, DYT1 dystonia exhibits low penetrance (~30%). As a result, the "secondhit" concept emerged, suggesting that additional environmental factors may be necessary to trigger the manifestation of dystonia. While significant progress has been made in understanding dystonia, its precise pathophysiology remains unclear. The basal ganglia, particularly the striatum, play a key role in controlling voluntary movements. It is hypothesized that an imbalance between the direct and indirect pathways may lead to the abnormal muscle contractions. However, the underlying mechanisms are not well understood. Changes in striatal synaptic plasticity and medium spiny neuron (MSN) dendritic complexity have been reported in animal models of dystonia. However, no studies have examined pathway-specific differences. This project aims to determine striatal structural plasticity in a mouse model of DYT1-Tor1A dystonia, before and 12 weeks after a “second-hit” (sciatic nerve crush) known to induce dystonia-like movements. Using high-resolution confocal imaging, we analyzed the dendritic morphology of D1-MSNs sparsely labeled with EYFP, by retro-orbital injection of AAV9.Ef1.DIO.EYFP in D1-Cre mice crossbred with DYT1 mice and wild-type littermates (WT). 3D reconstructions of D1-MSNs’ confocal images allowed for detailed quantification of dendritic parameters. Namely, 3D Sholl analysis, total dendritic length, number of dendrites, branching points, straightness, and soma volume. Our results show that, while an effect of the DYT1 mutation on dendritic complexity did not reach statistical significance, there was an increase in soma volume in DYT1 mice compared to WT controls, 12 weeks after a sciatic nerve crush. These findings suggest that torsinA dysfunction, in combination with a second-hit, affects the structural plasticity of D1-MSNs. Our study provides novel insights into the morphological abnormalities in D1- MSNs associated with DYT1 dystonia.
Abstract: Dystonia is a movement disorder characterized by involuntary and intermittent muscle contractions, leading to abnormal movements and postures. DYT-TOR1a dystonia (DYT1) is the most common hereditary form and it is caused by a mutation in the TOR1A gene. Despite its well-defined genetic cause, DYT1 dystonia exhibits low penetrance (~30%). As a result, the "secondhit" concept emerged, suggesting that additional environmental factors may be necessary to trigger the manifestation of dystonia. While significant progress has been made in understanding dystonia, its precise pathophysiology remains unclear. The basal ganglia, particularly the striatum, play a key role in controlling voluntary movements. It is hypothesized that an imbalance between the direct and indirect pathways may lead to the abnormal muscle contractions. However, the underlying mechanisms are not well understood. Changes in striatal synaptic plasticity and medium spiny neuron (MSN) dendritic complexity have been reported in animal models of dystonia. However, no studies have examined pathway-specific differences. This project aims to determine striatal structural plasticity in a mouse model of DYT1-Tor1A dystonia, before and 12 weeks after a “second-hit” (sciatic nerve crush) known to induce dystonia-like movements. Using high-resolution confocal imaging, we analyzed the dendritic morphology of D1-MSNs sparsely labeled with EYFP, by retro-orbital injection of AAV9.Ef1.DIO.EYFP in D1-Cre mice crossbred with DYT1 mice and wild-type littermates (WT). 3D reconstructions of D1-MSNs’ confocal images allowed for detailed quantification of dendritic parameters. Namely, 3D Sholl analysis, total dendritic length, number of dendrites, branching points, straightness, and soma volume. Our results show that, while an effect of the DYT1 mutation on dendritic complexity did not reach statistical significance, there was an increase in soma volume in DYT1 mice compared to WT controls, 12 weeks after a sciatic nerve crush. These findings suggest that torsinA dysfunction, in combination with a second-hit, affects the structural plasticity of D1-MSNs. Our study provides novel insights into the morphological abnormalities in D1- MSNs associated with DYT1 dystonia.
Descrição
Palavras-chave
Dystonia Medium spiny neurons Dendritic morphology