Abnormal expression of the eukaryotic translation elongation factor 1A (eEF1A) has been implicated in disease states such as motor neuron degeneration and cancer. Two variants of eEF1A are found in mammals, named eEF1A1 and eEF1A2. These two variants are encoded by different genes, produce proteins which are 92% identical but have very different patterns of expression. eEF1A1 is almost ubiquitously expressed while eEF1A2 is expressed only in specialised cell types such as motor neurons and muscle. A spontaneous mutation in eEF1A2 results in the wasted mouse phenotype which shows similar characteristics in the mouse to those seen in human motor neuron degeneration. This mutation has been shown to be a 15.8kb deletion resulting in the complete loss of the promoter region and first non coding exon of eEF1A2 which completely abolishes protein expression. The main aim of this project was to further investigate the role of eEF1A2 in motor neuron degeneration. Firstly, although the wasted phenotype is considered to be caused by a recessive mutation, I established a cohort of aged heterozygote mice to evaluate whether any changes are seen later in life that might model late onset motor neuron degeneration. A combination of behavioural tests and pathology was used to compare wild type and heterozygous mice up to 21 months of age. Whilst results indicate that there is no significant difference between ageing heterozygotes and wildtype controls, there is an indication that female heterozygote mice perform slightly worse that wildtype controls on the rotarod (a behavioural test for motor function). Secondly, I aimed to investigate the primary cause of the wasted pathology by generating transgenic wasted mice expressing neuronal eEF1A2 only. This would complement previous experiments in the lab which studied transgenic wasted mice expressing eEF1A2 in muscle only. Unfortunately the expression of eEF1A2 in the transgenic animals was not neuronal specific. However a transgenic line with expression of eEF1A2 in neurons and skeletal muscle but not cardiac muscle has been generated which clearly warrants further investigation. Thirdly, I wished to assess whether eEF1A2 has any role in human motor neuron degeneration. To achieve this, eEF1A2 expression was investigated in spinal cords from human motor neuron disease (MND) patients. Preliminary data suggests that motor neurons from some MND patients express significantly less eEF1A2 than motor neurons of control samples. Further work is required to confirm these findings. Finally, I investigated the individual roles of eEF1A1 and eEF1A2 in the heat shock response. I used RNAi to ablate each variant separately in cells and subsequently measured the ability of each variant individually to mount a heat shock response. Results indicate a clear role for eEF1A1 but not eEF1A2 in the induction of heat shock. This may explain in part why motor neurons exhibit a poor heat shock response as they express eEF1A2 and not eEF1A1. These experiments shed light on our understanding of the role of eEF1A2 in motor neuron degeneration and uncover many new avenues of future investigation.

O sistema visual lida com mudanças significativas na quantidade absoluta de fótons no meio ambiente, que varia 10 a 12 unidades logarítmicas ao longo de um dia. Parte desta versatilidade decorre da existência de fotorreceptores, bastonetes e cones, ativos em luminosidades médias diferentes, e outra parte é consequência de mecanismos de controle de ganho pós-receptorais, que ajustam a faixa dinâmica da retina à luminosidade média. Já na primeira sinapse visual, a atividade de muitos fotorreceptores converge para as células bipolares (BCs), neurônios de segunda ordem. Em mamíferos, supõe-se que o número de neurônios convergentes mantém-se relativamente fixo durante a vida adulta do organismo, embora a árvore dendrítica das BCs aumente de tamanho. No caso de peixes teleósteos, o grau de convergência neuronal para as BCs aumenta com a idade em função de neurogênese e sinaptogênese constantes. Como a relação entre a estrutura celular e o grau de convergência sináptica influencia a integração somática de sinais, estudamos os efeitos do crescimento celular acompanhado de variações na convergência sináptica no caso específico da BC ligada a bastonetes. Para tanto, desenvolvemos um modelo computacional deste tipo celular e dos bastonetes a ela conectados utilizando o ambiente de simulação NEURON, com base em dados de literatura e obtidos por nosso grupo de pesquisa a respeito de sua geometria, conectividade e biofísica, e simulamos diversos tipos de estimulação. Para mimetizar níveis escotópicos de luminosidade, estimulamos apenas um dos bastonetes convergindo para a BC modelo; para mimetizar níveis mesópicos, todos os bastonetes foram estimulados concomitantemente. Estas simulações foram realizadas primeiramente com um modelo de BC contendo apenas condutâncias sinápticas e passivas, para investigar o impacto da geometria celular na integração de sinais. A seguir, o modelo passou a incorporar condutâncias dependentes de voltagem permeáveis a potássio (K+) modeladas a partir de dados da literatura e do nosso grupo de pesquisa, para investigar o papel das mesmas no controle de ganho da sinapse entre BCs e bastonetes durante o crescimento celular. Os resultados destas simulações indicam que o aumento da árvore dendrítica da BC com o crescimento hiperpolariza seu potencial de repouso e aumenta as amplitudes de resposta, devido ao aumento da área de superfície de membrana contendo canais passivos com potencial de reversão negativo. Já o aumento da convergência de bastonetes para a BC despolariza seu potencial de repouso e diminui as amplitudes resposta, o que equivaleria a uma diminuição da sensibilidade 3 em células reais. Mais ainda, o aumento no grau de convergência contribui para a diminuição das latências de resposta da BC, ao passo que o crescimento celular aumenta as latências linearmente. A inserção de canais dependentes de voltagem nos terminais dendríticos da BC aproxima as amplitudes e diminui as latências de resposta de BCs com diferentes graus de convergência. Além disso, tais canais reduzem os efeitos decorrentes do crescimento celular descritos anteriormente, tornando a amplitude e latência de resposta independentes do tamanho da árvore dendrítica. Desse modo, canais de K+ dependentes de voltagem dendríticos estabilizam as amplitudes e latências de resposta da BC ao longo do crescimento, contribuindo para a coerência da mensagem passada para as outras camadas da retina e, posteriormente, para o cérebro. Estes resultados sugerem que correntes ativas são fundamentais não apenas para controlar o ganho das sinapses entre bastonetes e BCs em um mesmo estado de adaptação, mas também para estabilizar o potencial de repouso e velocidade e amplitudes de resposta dos neurônios ao longo do crescimento / The visual system deals with significant changes in the absolute quantity of photons in the environment, which vary 10 to 12 log units throughout a single day. Part of this versatility is due to the existence of different photoreceptors, rods and cones, which function at different mean light intensities, and due to post-receptor gain control mechanisms, which adjust the dynamic range of the retina to the mean luminosity. At the first visual synapse, the activity of many photoreceptors converges onto bipolar cells (BCs), second order neurons of the retina. In mammals, the degree of convergence is supposed to be constant throughout adult life, despite evidence of morphological changes in the dendritic structure of BCs. In teleost fish, however, the convergence of rods to BCs increases with age due to constant retinal neurogenesis and synaptogenesis. Since cellular structure and synaptic convergence influence somatic signal integration, we investigated the effects of cellular growth and synaptic convergence in the responses of the rod bipolar cell. We developed a computational model of a BC-rod circuitry within the NEURON simulation environment, based on literature data and on data collected by our own research group regarding the geometry, connectivity and biophysics of BCs. To simulate scotopic light levels, only one of the rods converging to the model BC was stimulated. Mesopic light levels were simulated by concomitantly stimulating all rods. We initially investigated the impact of cell geometry in somatic signal integration, by studying a model BC containing only passive and synaptic conductances. We subsequently inserted a voltage-gated potassium (K+) conductance in the dendritic tips of the model in order to investigate its role in controlling the gain of the rod-BC synapse during growth. Our results indicate that increasing the dendritic tree leads to hyperpolarization of the BC resting potential, due to the larger membrane surface containing the passive conductance, which has a negative reversal potential. Increasing rod convergence, on the other hand, depolarizes the BC resting potential and decreases response amplitudes, which would be equivalent to a decrease in sensitivity in a real cell. In addition, increases in convergence reduce response latencies, whereas cellular growth increases latencies linearly. The insertion of voltage-gated K+ conductances in the dendritic tips of the BC, in turn, aproximates the response amplitudes and decreases response latencies of BCs with different synaptic convergences. Moreover, voltage-gated conductances reduce the consequences of cellular growth, rendering response amplitudes and latencies independent of dendritic 5 tree size. These active conductances therefore contribute to signal consistency. Our results suggest that active currents not only control the gain of the rod-BC synapse in a given adaptive state, but also stabilize the BC resting potential, as well as response amplitude and latency during growth

No description available.

<p>On the 13th of June 2005 the Minister of Defence, Leni Björklund, was subjected to a formal complaint addressed to the Committee on the Constitution concerning her handling of a specific co-operation project with France. The project concerned the development of a technology demonstrator for an UCAV called Neuron. The reason for the complaint was that the Minister of Defence had failed to present the project to the parliament and thus bypassed a parliamentary decision. Such negligence might be considered unlawful under the Swedish Constitution. The issue became public during an unscheduled meeting with the Committee on Defence, a meeting that was arranged at the request of the Minister of Defence. During that meeting the Minister announced that the Government in a couple of days planned to take the decision to “go ahead” with the Neuron project without a formal decision by the Parliament. The then estimated cost for the project was about 700 million SEK. The “verdict” from the Committee on the Constitution was “not guilty” according to the Constitution. The Committee on the Constitution limits its investigations to the relation between the Parliament and the Government, which is its main task. The purpose of my essay is to investigate the relation between  the Government and the Swedish Armed Forces. This investigation is conducted in order to find out what kind of role the Armed Forces as a Government Agency has played in the formulation of defence policy regarding the Neuron project. The foundation of a representative democratic system is based on the premise that the formulation of political objectives is the exclusive right of politicians. Only the elected politicians are supposed to have this power, since they are performing their duties on a mandate from the electorate, the people. The formulation of political objectives is, according to this foundation, not something that civil servants, in or out of uniform, should be doing. If and when that however happens we are facing what is normally called “a democratic black hole”.  </p><p>In order to fulfil the purpose of my essay I investigate the communication between the Government and the Armed Forces. The empirical study is performed on two kinds of documents from the Armed Forces. These documents are regularly used as basis for the Government’s decisions and propositions to the Parliament. The first kind is the Armed Force’s yearly reports concerning Long Term Planning, the second kind is documents that the Government needs for the yearly Budgetary Proposition. Both documents are wholly or partly prepared according to instructions from the Government.</p> / <p>Den 13 juni 2005 blir försvarsminister Leni Björklund KU - anmäld för sin sätt att hantera ett svenskt deltagande i projektet Neuron. Neuron-projektet handlar om försvarsmaterielsamarbete med Frankrike om att utveckla en demonstrator av en UCAV, obemannad beväpnad flygfarkost, som kallas Neuron. Anmälan handlar om att försvarsministern och därmed regeringen inte har givit riksdagen möjlighet att fatta beslut om Neuron-projektet. Regeringen hade inte med Neuron-projektet i någon proposition som riksdagen har kunnat ta ställning till, innan den 13 juni 2005. Hela frågan uppdagas när försvarsministern den 7 juni 2005 sammankallar riksdagens försvarsutskott. Vid detta möte informerar försvarsministern utskottets ledamöter om att regeringen har för avsikt att två dagar senare fatta beslut om att inleda samarbetet med Frankrike om Neuron-projektet som då ska kosta ca. 700 miljoner kronor. När KU har granskat frågan färdigt, våren 2006 blir försvarsministern trots allt inte fälld för ”brott” mot Regeringsformen. KU granskade enbart relationen mellan regeringen och riksdagen. Det jag gör i uppsatsen är att granska relationen mellan regeringen och Försvarsmakten. Detta görs för att pröva de tidigare leden i det som kallas den demokratiska styrkedjan och som beskriver hur makt och ansvar bör gå till i en folkstyrd demokrati. Den demokratiska styrkedjan består av: Folket, Riksdagen, Regeringen, Förvaltningen</p><p>Med förvaltningen menas myndigheterna. Styrningen, dvs. maktutövningen, förutsätts gå från vänster till höger, medan ansvarigheten skall gå i den motsatta riktningen. Om det uppstår brott i kedjan eller om den ’börjar gå baklänges’ uppstår något av en ’demokratins svarta hål’.  I Regeringsformen stadgas att regeringen styr riket och att myndigheterna, exempelvis Försvarsmakten, lyder under regeringen. Grundtanken vad gäller relationen mellan regering och myndigheter är att politikerna styr genom att formulera mål och riktlinjer för myndigheterna, medan myndigheterna genomför de politiska målen. Kedjan går baklänges om det istället skulle vara så att myndigheterna börjar formulera målen.</p><p>Efter KU:s granskning stod det klart att det inte fanns något formellt problem mellan riksdagen och regeringen när det gäller hur makt och ansvar hanterades. KU granskade inte, som nämnts ovan, relationen mellan regeringen och Försvarsmakten vilket är det jag gör i uppsatsen. I uppsatsen undersöker jag de underlag Försvarsmakten överlämnar till regeringen. Dessa är årliga budgetunderlag och PerP-rapporter. Budgetunderlagen utarbetas helt efter regeringens anvisningar medan PerP-rapporterna har en dubbelroll. De är både Försvarsmaktens egen perspektivplanering och i delar utarbetade efter regeringens anvisningar.</p>

On the 13th of June 2005 the Minister of Defence, Leni Björklund, was subjected to a formal complaint addressed to the Committee on the Constitution concerning her handling of a specific co-operation project with France. The project concerned the development of a technology demonstrator for an UCAV called Neuron. The reason for the complaint was that the Minister of Defence had failed to present the project to the parliament and thus bypassed a parliamentary decision. Such negligence might be considered unlawful under the Swedish Constitution. The issue became public during an unscheduled meeting with the Committee on Defence, a meeting that was arranged at the request of the Minister of Defence. During that meeting the Minister announced that the Government in a couple of days planned to take the decision to “go ahead” with the Neuron project without a formal decision by the Parliament. The then estimated cost for the project was about 700 million SEK. The “verdict” from the Committee on the Constitution was “not guilty” according to the Constitution. The Committee on the Constitution limits its investigations to the relation between the Parliament and the Government, which is its main task. The purpose of my essay is to investigate the relation between  the Government and the Swedish Armed Forces. This investigation is conducted in order to find out what kind of role the Armed Forces as a Government Agency has played in the formulation of defence policy regarding the Neuron project. The foundation of a representative democratic system is based on the premise that the formulation of political objectives is the exclusive right of politicians. Only the elected politicians are supposed to have this power, since they are performing their duties on a mandate from the electorate, the people. The formulation of political objectives is, according to this foundation, not something that civil servants, in or out of uniform, should be doing. If and when that however happens we are facing what is normally called “a democratic black hole”.   In order to fulfil the purpose of my essay I investigate the communication between the Government and the Armed Forces. The empirical study is performed on two kinds of documents from the Armed Forces. These documents are regularly used as basis for the Government’s decisions and propositions to the Parliament. The first kind is the Armed Force’s yearly reports concerning Long Term Planning, the second kind is documents that the Government needs for the yearly Budgetary Proposition. Both documents are wholly or partly prepared according to instructions from the Government. / Den 13 juni 2005 blir försvarsminister Leni Björklund KU - anmäld för sin sätt att hantera ett svenskt deltagande i projektet Neuron. Neuron-projektet handlar om försvarsmaterielsamarbete med Frankrike om att utveckla en demonstrator av en UCAV, obemannad beväpnad flygfarkost, som kallas Neuron. Anmälan handlar om att försvarsministern och därmed regeringen inte har givit riksdagen möjlighet att fatta beslut om Neuron-projektet. Regeringen hade inte med Neuron-projektet i någon proposition som riksdagen har kunnat ta ställning till, innan den 13 juni 2005. Hela frågan uppdagas när försvarsministern den 7 juni 2005 sammankallar riksdagens försvarsutskott. Vid detta möte informerar försvarsministern utskottets ledamöter om att regeringen har för avsikt att två dagar senare fatta beslut om att inleda samarbetet med Frankrike om Neuron-projektet som då ska kosta ca. 700 miljoner kronor. När KU har granskat frågan färdigt, våren 2006 blir försvarsministern trots allt inte fälld för ”brott” mot Regeringsformen. KU granskade enbart relationen mellan regeringen och riksdagen. Det jag gör i uppsatsen är att granska relationen mellan regeringen och Försvarsmakten. Detta görs för att pröva de tidigare leden i det som kallas den demokratiska styrkedjan och som beskriver hur makt och ansvar bör gå till i en folkstyrd demokrati. Den demokratiska styrkedjan består av: Folket, Riksdagen, Regeringen, Förvaltningen Med förvaltningen menas myndigheterna. Styrningen, dvs. maktutövningen, förutsätts gå från vänster till höger, medan ansvarigheten skall gå i den motsatta riktningen. Om det uppstår brott i kedjan eller om den ’börjar gå baklänges’ uppstår något av en ’demokratins svarta hål’.  I Regeringsformen stadgas att regeringen styr riket och att myndigheterna, exempelvis Försvarsmakten, lyder under regeringen. Grundtanken vad gäller relationen mellan regering och myndigheter är att politikerna styr genom att formulera mål och riktlinjer för myndigheterna, medan myndigheterna genomför de politiska målen. Kedjan går baklänges om det istället skulle vara så att myndigheterna börjar formulera målen. Efter KU:s granskning stod det klart att det inte fanns något formellt problem mellan riksdagen och regeringen när det gäller hur makt och ansvar hanterades. KU granskade inte, som nämnts ovan, relationen mellan regeringen och Försvarsmakten vilket är det jag gör i uppsatsen. I uppsatsen undersöker jag de underlag Försvarsmakten överlämnar till regeringen. Dessa är årliga budgetunderlag och PerP-rapporter. Budgetunderlagen utarbetas helt efter regeringens anvisningar medan PerP-rapporterna har en dubbelroll. De är både Försvarsmaktens egen perspektivplanering och i delar utarbetade efter regeringens anvisningar.

For decades electrophysiologists have recorded and characterized the biophysical properties of a rich diversity of neuron types. This diversity of neuron types is critical for generating functionally important patterns of brain activity and implementing neural computations. In this thesis, I developed computational methods towards quantifying neuron diversity and applied these methods for understanding the functional implications of within-type neuron variability and across-type neuron diversity. First, I developed a means for defining the functional role of differences among neurons of the same type. Namely, I adapted statistical neuron models, termed generalized linear models, to precisely capture how the membranes of individual olfactory bulb mitral cells transform afferent stimuli to spiking responses. I then used computational simulations to construct virtual populations of biophysically variable mitral cells to study the functional implications of within-type neuron variability. I demonstrate that an intermediate amount of intrinsic variability enhances coding of noisy afferent stimuli by groups of biophysically variable mitral cells. These results suggest that within-type neuron variability, long considered to be a disadvantageous consequence of biological imprecision, may serve a functional role in the brain. Second, I developed a methodology for quantifying the rich electrophysiological diversity across the majority of the neuron types throughout the mammalian brain. Using semi-automated text-mining, I built a database, Neuro- Electro, of neuron type specific biophysical properties extracted from the primary research literature. This data is available at http://neuroelectro.org, which provides a publicly accessible interface where this information can be viewed. Though the extracted physiological data is highly variable across studies, I demonstrate that knowledge of article-specific experimental conditions can significantly explain the observed variance. By applying simple analyses to the dataset, I find that there exist 5-7 major neuron super-classes which segregate on the basis of known functional roles. Moreover, by integrating the NeuroElectro dataset with brain-wide gene expression data from the Allen Brain Atlas, I show that biophysically-based neuron classes correlate highly with patterns of gene expression among voltage gated ion channels and neurotransmitters. Furthermore, this work lays the conceptual and methodological foundations for substantially enhanced data sharing in neurophysiological investigations in the future.

Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. Whether TSA specifically targets the upregulation of the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice is unclear. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-Smn mediated pathway. Daily intraperitoneal injection of TSA from postnatal day 12 to 25 was performed in the Smn2B/- mice and littermate controls. Previous work from our laboratory demonstrated that treatment with TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/-mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Here, we have shown that TSA treatment does not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. Further, qPCR analysis revealed no changes in the level of Smn transcripts in the brain or spinal cord of TSA-treated SMA mice. Similarly, western blot analysis revealed no significant increase in Smn protein levels in the brain, spinal cord, hind limb muscle, heart muscle, or the liver of TSA treated Smn2B/- mice. However, TSA has beneficial effects in the muscles of Smn2B/- mice and improves motor behavior and myofiber size. TSA improves muscle development by enhancing the activity of myogenic regulatory factors independent of the Smn gene. The beneficial effect of TSA is therefore likely through an Smn-independent manner. Identification of these protective pathways will be of therapeutic value for the treatment of SMA.

No description available.

In recent years it has become apparent that neuronal development and function relies not just on the regulation of transcription but also on post-transcriptional events. Two prevalent mRNA-based regulatory mechanisms in neurons are asymmetric mRNA localisation and the generation of different 3’UTR isoforms by alternative polyadenylation (APA). While experiments in mammalian systems indicate that subcellular mRNA localisation plays an important role in regulating local expression of proteins in neuronal processes, little is known about how mRNAs reach their destinations. It has been proposed that APA allows the production of mRNA isoforms with different roles. However, the importance of 3’UTR extensions has not been addressed in detail, particularly at the organismal level. In my PhD, I investigated the mechanisms of mRNA localisation and functional consequences of APA using the Drosophila embryonic nervous system as a genetically tractable model. I screened for mRNAs that localise in embryonic axons using an available transgenic library of 3’UTR sequences, as well as publically available in situ hybridisation data. I found that Ankyrin2 (Ank2) mRNA localises in Drosophila embryonic sensory neurons, and showed that this is dependent on the kinesin-1 motor and microtubules. These data reveal an active mRNA transport system in embryonic neurons. I also showed that the Ank2 mRNA has an extended 3’UTR that is found in axons, suggesting that APA could be relevant to axonal functions of Ank2. I demonstrated that while mRNA molecules could still localise to axons upon CRISPR-Cas9-mediated deletion of the Ank2 3’UTR extension, a fraction of the mutant embryos had a disrupted nervous system. Interestingly, embryos that lack the ability to make Ank2 protein have an overtly normal embryonic nervous system. This observation reveals that the extension does not simply promote Ank2 protein function. Further experiments revealed that the extended 3’UTR is required for efficient locomotion of adult flies. While the exact function of the Ank2 3’UTR extension requires future investigation, I show that it is unlikely to be associated with the trafficking of associated proteins into axons. RNA affinity purifications from embryonic extracts provide evidence that the 3’UTR extension selectively binds conserved RNA-binding proteins. I speculate that the extension plays a role in regulating axonal morphogenesis by regulating the relative expression level of different Ank2 protein isoforms.

Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. Whether TSA specifically targets the upregulation of the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice is unclear. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-Smn mediated pathway. Daily intraperitoneal injection of TSA from postnatal day 12 to 25 was performed in the Smn2B/- mice and littermate controls. Previous work from our laboratory demonstrated that treatment with TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/-mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Here, we have shown that TSA treatment does not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. Further, qPCR analysis revealed no changes in the level of Smn transcripts in the brain or spinal cord of TSA-treated SMA mice. Similarly, western blot analysis revealed no significant increase in Smn protein levels in the brain, spinal cord, hind limb muscle, heart muscle, or the liver of TSA treated Smn2B/- mice. However, TSA has beneficial effects in the muscles of Smn2B/- mice and improves motor behavior and myofiber size. TSA improves muscle development by enhancing the activity of myogenic regulatory factors independent of the Smn gene. The beneficial effect of TSA is therefore likely through an Smn-independent manner. Identification of these protective pathways will be of therapeutic value for the treatment of SMA.