The onset of abnormal movements in DYT1 dystonia is between childhood and adolescence, although it is unclear why clinical manifestations appear during this developmental period. Plasticity at corticostriatal synapses is critically involved in motor memory. In the Tor1a +/D gag DYT1 dystonia mouse model, long-term potentiation (LTP) appeared prematurely in a critical developmental window in striatal spiny neurons (SPNs), while long-term depression (LTD) was never recorded. Analysis of dendritic spines showed an increase of both spine width and mature mushroom spines in Tor1a +/Dgag neurons, paralleled by an enhanced AMPA receptor (AMPAR) accumulation. BDNF regulates AMPAR expression during development. Accordingly, both proBDNF and BDNF levels were significantly higher in Tor1a +/Dgag mice. Consistently, antagonism of BDNF rescued synaptic plasticity deficits and AMPA currents. Our findings demonstrate that early loss of functional and structural synaptic homeostasis represents a unique endophenotypic trait during striatal maturation, promoting the appearance of clinical manifestations in mutation carriers.

A mutation of the DYT1 gene, which codes for torsinA, has been identified as the cause of one form of autosomal dominantly inherited dystonia. TorsinA immunohistochemistry was used to examine a case of DYT1, and several cases of non-DYT1, dystonia. No evidence was found for alterations of immunoreactivity at the light microscopic level, specifically neither cytoplasmic aggregations nor colocalization of torsinA immunoreactivity with a marker for endoplasmic reticulum. These findings contrast with results of recent cell culture studies of torsinA.

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Childhood-onset dystonia is an autosomal dominant movement disorder associated with a three base pair (GAG) deletion mutation in the DYT1 gene. This gene encodes a novel ATP-binding protein called torsinA, which in the central nervous system is expressed exclusively in neurons. Neither the function of torsinA nor its role in the pathophysiology of DYT1 dystonia is known. In order to better understand the cellular functions of torsinA, we established PC12 cell lines overexpressing wild-type or mutant torsinA and subjected them to various conditions deleterious to cell survival. Treatment of control PC12 cells with an inhibitor of proteasomal activity, an oxidizing agent, or trophic withdrawal, resulted in cell death, whereas PC12 cells that overexpressed torsinA were significantly protected against each of these treatments. Overexpression of mutant torsinA failed to protect cells against trophic withdrawal. These results suggest that torsinA may play a protective role in neurons against a variety of cellular insults.

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Prin finalizarea cercetarii de fata ne-am propus sa oferim cadrelor didactice instrumente de lucru in organizarea activitatilor pe echipe si mai ales modalitati de evaluare a procesului invatarii prin cooperare. Iar la sfarsitul stradaniilor lor sa ajunga la acea echipa de vis (fie ea in randul elevilor, fie a cadrelor didactice), asa cum i-au numit cercetatorii de la NASA pe cei care au colaborat la sute de mii de kilometri distanta pentru salvarea echipajului navei cosmice Odyssey in 1970. Numit „un esec reusit” misiunea Apollo 13 ramane un exemplu de cooperare pentru orice domeniu de activitate, iar concluzia nu poate fi decat urmatoarea: „Momentul potrivit pentru a va construi echipa nu este in mijlocul unei provocari pe viata si pe moarte, ci cu mult inainte ca o asemenea situatie sa apara. Daca nu o aveti deja, incepeti chiar astazi sa o construiti in asa fel incat atunci cand apare o provocare majora, dumneavoastra si echipa dumneavoastra sa fiti pregatiti”.