Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that causes motor, visual, and sensory symptoms. Patients also experience constipation, which is not yet understood, but could involve dysfunction of the enteric nervous system (ENS). Autoimmune targeting of the ENS occurs in other autoimmune diseases that exhibit gastrointestinal (GI) symptoms, and similar mechanisms could lead to GI dysfunction in MS. Here, we characterize GI dysmotility in the experimental autoimmune encephalomyelitis (EAE) model of MS and test whether autoantibodies targeting the ENS are present in the serum of MS patients. Male SJL or B6 mice were induced with EAE by immunization against PLP139-151, MOG35-55, or mouse spinal cord homogenate, and monitored daily for somatic motor symptoms. EAE mice developed GI symptoms consistent with those observed in MS. In vivo motility analysis demonstrated slower whole GI transit, and decreased colonic propulsive motility. EAE mice had faster rates of gastric emptying, with no changes in small intestinal motility. Consistent with these results, ex vivo evaluation of isolated colons demonstrated that EAE mice have slower colonic migrating myoelectric complexes and slow wave contractions. Immunohistochemistry of EAE colons exhibited a significant reduction in GFAP area of ENS ganglia, with no changes in HuD, S100, or neuron numbers. To test whether antibodies in MS bind to ENS structures, we collected serum samples from MS patients with constipation and without constipation, and healthy control patients without constipation. Immunoreactivity was tested using indirect immunofluorescence by applying serum samples to guinea pig ENS tissue. MS serum exhibited significantly higher immunoreactivity against guinea pig ENS than control patients, which was particularly evident in MS patients who did not experience constipation. There was no significant difference in immunoreactivity between MS patients with and without constipation. Targets of human MS and mouse EAE serum include enteric glia and neurons. Taken together, these data validate EAE as a model for constipation in MS, and support the concept that this symptom involves changes within the neuromuscular system of the colon. EAE mice develop symptoms consistent with constipation that affects functional ENS networks and may result in structural or phenotypic changes at the cellular level. Serum immunoreactivity suggests that autoantibodies could play a role in the development of constipation in MS by targeting the ENS itself.

The voltage gated potassium channel Kv1.2 plays a key role in the central nervous system and mutations in Kv1.2 cause neurological disorders such as epilepsies and ataxias. In the cerebellum, regulation of Kv1.2 is coupled to learning and memory. We have previously shown that blocking Kv1.2 by infusing its specific inhibitor tityustoxin-kα (TsTX) into the lobulus simplex of the cerebellum facilitates eyeblink conditioning (EBC) and that EBC itself modulates Kv1.2 surface expression in cerebellar interneurons. The metabotropic glutamate receptor mGluR1 is required for EBC although the molecular mechanisms are not fully understood. Here we show that infusion of the mGluR1 agonist (S)-3,5-dihydroxyphenylglycine (DHPG) into the lobulus simplex of the cerebellum mimics the facilitating effect of TsTX on EBC. We therefore hypothesize that mGluR1 could act, in part, through suppression of Kv1.2. Earlier studies have shown that Kv1.2 suppression involves channel tyrosine phosphorylation and endocytocytic removal from the cell surface. In this study we report that an excitatory chemical stimulus (50mM K+-100µM glutamate) applied to cerebellar slices enhanced Kv1.2 tyrosine phosphorylation and that this increase was lessened in the presence of the mGluR1 inhibitor YM298198. More direct evidence for mGluR1 modulation of Kv1.2 comes from our finding that selective activation of mGluR1 with DHPG reduced the amount of surface Kv1.2 detected by cell surface biotinylation in cerebellar slices. To determine the molecular pathways involved we used an unbiased mass spectrometry-based proteomics approach to identify Kv1.2-protein interactions that are modulated by mGluR1. Among the interactions enhanced by DHPG were those with PKC-γ, CaMKII, and Gq/G11, each of which had been shown in other studies to co-immunoprecipitate with mGluR1 and contribute to its signaling. Of particular note was the interaction between Kv1.2 and PKC-γ since in HEK cells and hippocampal neurons Kv1.2 endocytosis is elicited by PKC activation. We found that activation of PKCs with PMA reduced surface Kv1.2, while the PKC inhibitor Go6983 attenuated the reduction in surface Kv1.2 levels elicited by DHPG and PMA, suggesting that the mechanism by which mGluR1 modulates cerebellar Kv1.2 likely involves PKC. mGluR1 has been shown to signal independently of the agonist through a constitutively active, protein kinase A-dependent pathway in the cerebellum. Using HEK293 cells we show that co-expression of mGluR1 increases the surface expression levels of Kv1.2. This effect occurs in absence of mGluR1 agonists and in the presence of a noncompetitive mGluR1 inhibitor YM298198. Co-expression of known downstream effectors of the agonist driven mGluR1 pathway such as PKC-γ, CaMKIIα, Grid2 had no effect on Kv1.2 surface expression or on the ability of mGluR1 agonist to modulate that expression. In contrast, the inverse agonist BAY 36-7620 significantly reduced the mGluR1 effect on Kv1.2 surface expression, as did pharmacological inhibition of PKA with KT5720. Therefore, mGluR1 is involved in regulation of surface Kv1.2 via dual mechanisms, the agonist dependent mechanism reduces surface Kv1.2 via PKC, while agonist independent constitutive mechanism increases surface Kv1.2 via PKA.

Schizophrenia is a severe mental disorder affecting ~1% of world population. Two G protein coupled receptors (GPCRs): Gi-coupled dopamine D2 receptor (D2R), and Gq-coupled serotonin 2A receptor (2AR), are targeted by the typical and atypical antipsychotic drugs to treat schizophrenia. These two receptors have been shown to co-localize in brain regions relevant to schizophrenia, including the ventral tegmental area (VTA), striatum, and prefrontal cortex (PFC). Studies in our lab characterized the integrated signaling of the D2R-2AR heteromer and found that both the Gi activity of D2R and the Gq activity of 2AR were potentiated in response to dopamine (DA) and serotonin (5-HT), whereas the potency of the typical antipsychotic drug (APD) haloperidol antagonizing Gi and Gq signaling was also enhanced. Using a peptide mimicking the transmembrane (TM) domain 5 of D2R, we showed disruption of the formation and function of the D2R-2AR heteromer in heterologous systems and ex vivo brain slices. Our functional and mutagenesis data suggested that D2R and 2AR heteromerize though a symmetric TM5,6-TM5,6 interface, and a network of Pi-Pi stacking interaction among eight conserved aromatic residues of D2R and 2AR may underlie the mechanism for the functional cross-talk between D2R and 2AR. Based on these results, we built a structural model for the D2R-2AR heteromer recapitulating its functional cross-talk characteristics. We are presently pursuing behavioral experiments to investigate the effectiveness of antipsychotic drugs on the function of the D2R-2AR heteromer in animal models of psychosis. Our overall study shows a dual role of the D2R-2AR heteromer in schizophrenia-associated psychosis and sheds light on the development of future therapeutic drugs for schizophrenia and other psychotic diseases.

Selective Mu Opioid Receptor (MOR) antagonists possess immense potential in the treatment of opioid abuse/addiction. Utilizing the “message-address” concept, our laboratory reported a novel, reversible, non-peptide MOR selective antagonist 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4՛-pyridyl)carboxamido]morphinan (NAP). Molecular modeling studies revealed that the selectivity of NAP for the MOR is because of a π-π stacking interaction of its pyridine ring with the Trp318residue in theMOR. Pharmacological characterization showed that NAP is a P-glycoprotein substrate, thereby limiting its use in the treatment of opioid abuse/addiction. Thus, to modify NAP, we replaced the pyridine ring with its isosteric counterpart thiophene. Isosteric replacement could lead to development of compounds with different pharmacologic properties. Additionally, exploring other ring systems would diversify and enrich our library of compounds and aid in establishing a comprehensive structure-activity relationship. Therefore, newly synthesized compounds included thiophene derivatives of 6α/β-naltrexamine with potential to be used in the treatment of opioid abuse/addiction. Preliminary in vivo screening revealed that compounds 8 and 11 could be acting as antagonists. To aid in the design and synthesis of newer generation of MOR selective analogs, a 3-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Comparative Molecular Field Analysis (CoMFA) on 6β-N-heterocyclic substituted naltrexamine derivatives was conducted. After rigorous optimizations, the best CoMFA model possessed low predictive power. Results obtained suggested that small structural changes could lead to significant change in binding modes of these ligands. To further validate this observation, molecular docking studies were performed which revealed that these ligands indeed possessed multiple distinct binding modes thereby offering rationale for the CoMFA results. Thus, overall this study furnished useful information about the complexity of protein-ligand interactions which will aid in designing more potent and selective MOR ligands.

Questions remain about the range of abilities autistic children possess and what constitutes effective treatment. Strength-based intervention contrasts with traditional autistic intervention approaches that focus on children's deficits. Studies on strength-based intervention approaches have not revealed how children's strengths are identified and have not used the insights of parents for this purpose. Neurodiversity serves as the conceptual framework because the tenets of neurodiversity align with those of strength-based approaches and hold that autism is a variation of the human condition rather than a disability. The purpose of this qualitative interpretive phenomenological study was to explore how the parent-identified strengths of autistic children may act as the basis for the advancement of strength-based intervention. The research questions focused on identifying the strengths of autistic children through semistructured interviews with 15 parents of high-functioning autistic children, who were recruited using purposive sampling. Data were analyzed using a three-level method, and six themes emerged: Routine, Caring for Others, Relationship with Parent, Intervention in School, Therapy, and Outlook for the Future. Practical implications for community psychology include development of strength-based approaches based on altruism, parent-child relationships, and positive outlooks for the future. Further research is recommended on caring for others and displaying affection in relation to strength-related constructs, such as resiliency and growth. Effective strength-based interventions may help autistic children develop based on their strengths, leading to positive social change.

The current shortage of clinical sites for neurodiagnostic technology (NDT) students is limiting enrollments and subsequently limiting graduates from NDT schools in the U.S. A lack of knowledge or consensus concerning the use of educational technology in NDT clinical skills training prompted this investigation. The purpose of this study was to explore the use of educational technology in providing NDT clinical skill training. This qualitative Delphi study was guided by experiential learning theory and cognitive constructionist epistemology. Thirty expert panelists were recruited to rate the effectiveness of educational technology methods in addressing neurodiagnostic competencies for electroencephalography. Twenty-four completed round one, twenty-two completed round two and nineteen completed the third and final round. The competencies were derived by combining national competencies or practice analysis from the United States, Australia, Canada and the United Kingdom for neurodiagnostic technologists performing electroencephalography (EEG). Results of the three rounds of the Delphi study were processed using the mean value and interquartile deviation for evaluation of consensus. Consensus among the expert panelists supported the potential effectiveness of educational technology to address neurodiagnostic graduate competencies for technologists performing EEG. In conclusion, the expert panel consensus was NDT clinical skills for performing EEG can be addressed using educational technology, followed by a post-graduate clinical residency. Using educational technology and a post-graduate residency could increase school capacity. An increase in graduate numbers would help sustain the existing schools, better supply the profession, and increase public access to quality neurodiagnostic care.

Friedreich's Ataxia (FA) is an autosomal-recessive, neurodegenerative disease characterized by progressive lower extremity muscle weakness and sensory loss, balance deficits, limb and gait ataxia, and dysarthria. FA is considered a sensory ataxia because the dorsal root ganglia and spinal cord dorsal columns are involved early in the disease, whereas the cerebellum is affected later. Balance deficits and gait ataxia are often evaluated clinically and in research using clinical rating scales. Recently, quantitative tools such as the Biodex Balance System SD and the GAITRite Walkway System have become available to objectively assess balance and gait, respectively. However, there are limited studies using instrumented measures to quantitatively assess and characterize balance and gait disturbances in FA, and longitudinal, quantitative analyses of both balance and gait have not been investigated in this patient cohort. The purpose of the present study was to characterize gait patterns of adults with FA and to identify changes in gait and balance over time using clinical rating scales and quantitative measures. Additionally, this study investigated the relationship between disease duration, clinical rating scale scores and objective measures of gait and balance. This study used a longitudinal research design to investigate changes in balance and gait in 8 adults with genetically confirmed FA and 8 healthy controls matched for gender, age, height, and weight. Subjects with FA were evaluated using the Berg Balance Scale (BBS), the Friedreich's Ataxia Rating Scale (FARS) and instrumented gait and balance measures at baseline, 6 months, 12 months and 24 months. Controls underwent the same tests at baseline and 12 months. Gait parameters were measured utilizing the GAITRite Walkway system with a focus on gait velocity, cadence, step and stride lengths, step and stride length variability and percent of the gait cycle in swing, stance and double limb support. Balance was assessed using the BBS and the Biodex Balance System; the latter included tests of postural stability and limits of stability. At baseline, there were significant differences in gait and balance parameters, BBS scores and FARS total scores between FA subjects and controls as determined using paired t-tests (p This is the first longitudinal study to demonstrate changes over time in gait and balance of adults with FA using both quantitative measures and clinical rating scales. This study provided a detailed characterization of the gait pattern and balance of adults with FA. The GAITRite Walkway system proved to be a sensitive measure, and able to detect subtle changes in gait parameters over time in adults with FA. In addition, the BBS was an appropriate and sensitive assessment to detect changes in static and dynamic balance in this patient cohort. Finally, results revealed a strong and consistent relationship between clinical rating scale scores, postural stability indices, limits of stability scores, and step and stride length variability in individuals with FA.

Les traumatismes médullaires, ainsi que les myopathies, les accidents vasculaires cérébraux ou les amputations peuvent entraîner de très lourds handicaps où la commande motrice ne peut plus être exécutée correctement. Les interfaces cerveau-machine ont été développées pour contrecarrer ces déficits. La plupart des groupes de recherche travaillant dans le domaine ont conçu des interfaces qui tentent de reconstruire un mouvement à partir de l'activité neuronale du cerveau. Dans notre cas, nous attaquons le problème différemment en conditionnant un neurone ou un petit nombre d'entre eux dans le cortex moteur de rats éveillés afin qu'ils contrôlent la vitesse d'un actuateur en une dimension en augmentant ou en diminuant leur taux de décharge. Dans ce protocole, connaître l'espace initial de codage des neurones conditionnés n'était pas un prérequis. Nous avons observé que l'activité de la plupart des neurones pouvait être modulée par conditionnement opérant, et pouvaient contrôler en temps réel et pendant plusieurs secondes la position d'une bouteille contenant une récompense liquide située en face de l'animal. De plus, pendant la période d'apprentissage, les neurones conditionnés ont affiché des propriétés spéciales comparées aux autres neurones non conditionnés, en termes de variabilité du taux de décharge, de latence de la réponse et de force de la modulation. Cela constitue la première démonstration d'un outil externe contrôlé en temps réel par des neurones conditionnés devant ajuster leur activité selon des objectifs constamment redéfinis.

La presencia de glucógeno en las neuronas ha sido motivo de controversia durante las pasadas décadas. Sin embargo, está aceptado que las neuronas expresan la maquinaria necesaria para sintetizar glucógeno, pero no para degradarlo. La presencia de la glucógeno sintasa (GS) en las neuronas es un misterio y no existe ningún estudio que analice cuál es su función fisiológica en este tipo neuronal. Recientemente se ha establecido un paralelismo entre la GS neuronal y el caballo de Troya, ya que múltiples estudios han demostrado que una hiper-activación de la GS y la consecuente acumulación de glucógeno desencadenan la entrada en apoptosis. A pesar de ello, la neurona gasta energía para su transcripción y traducción, lo que hace pensar que su presencia en la neurona es importante para su correcto funcionamiento. Los objetivos de esta tesis doctoral son los siguientes: 1. Caracterización del metabolismo de glucógeno y de su presencia en neuronas. 2. Estudio de la maquinaria de degradación de glucógeno en neuronas y su regulación en hipoxia 3. Análisis de la síntesis de glucógeno en neuronas expuestas a hipoxia. 4. Evaluación de la función biológica de la GS en neuronas bajo condiciones de hipoxia. Los resultados de esta tesis revelan que las neuronas tienen una síntesis de glucógeno activa, y, además, lo acumulan en condiciones basales. Además, poseen la maquinaria necesaria para la degradación de glucógeno y degradan sus propias reservas en condiciones de hipoxia. La capacidad neuronal de degradación de glucógeno está presente en una situación in vivo, ya que las neuronas del modelo Drosophila melanogaster movilizan sus reservas en condiciones de hipoxia, y las neuronas de Purkinje en el ratón lo hacen tras una anoxia post-mortem prolongada. La maquinaria de degradación del polisacárido, desconocida hasta el momento, está mediada por la expresión de la glucógeno fosforilasa (GP). Las neuronas expresan la isoforma cerebral del enzima, pero no la muscular, como en el caso de los astrocitos. Esta isoforma está presente tanto en neuronas en cultivo como en neuronas procedentes de cortes de cerebro de ratón adulto. La hipoxia causa la defosforilación y activación de la GS. La GS sintetiza glucógeno activamente, aunque los niveles netos del polisacárido disminuyen en hipoxia. Por tanto, está teniendo lugar un ciclo aparentemente fútil en donde la síntesis y degradación se encuentran activas. Finalmente se ha demostrado que el metabolismo del glucógeno forma parte de la maquinaria de protección que activa la neurona para resistir a la hipoxia. En consecuencia, las neuronas que carecen la GS tienen una mortalidad más elevada que aquellas que sí que expresan el enzima. En el modelo de la mosca, el metabolismo del glucógeno neuronal también juega un papel en la tolerancia a la hipoxia y moscas con niveles reducidos de GS específicamente en la neurona muestran un empeoramiento en la respuesta tras un período de bajo oxígeno. En conclusión, esta tesis presenta evidencias de que las neuronas poseen un metabolismo activo de glucógeno que, además, juega un papel clave en la tolerancia de estas células a condiciones de hipoxia. / The presence of glycogen in neurons has been a matter of debate for the past decades. However, it is accepted that neurons express the necessary machinery to synthesize glycogen, but not for degrading it. The presence of Glycogen Synthase (GS) in neurons is a mystery and there is no study which approaches its physiological function in this cellular type. Recently a parallelism has been drawn between GS and the Trojan horse, since several studies have shown that an over-activation of GS and an accumulation of glycogen cause apoptosis in the neurons. Nevertheless, neurons waste energy for transcribing and synthesizing the protein, which suggests that its presence might be important for the normal functioning of the neurons. The aims of the thesis are the follows 1) Characterization of glycogen metabolism and its presence in neurons 2) Study of the glycogen degradation machinery in neurons and its regulation in hypoxia 3) Analysis of the synthesis of glycogen in neurons exposed to hypoxia 4) Evaluation of the biological function of GS in neurons under hypoxia conditions The results of this thesis reveal that there is an active glycogen synthesis under normal conditions. In addition, they express the necessary machinery to degrade the polysaccharide and degrade it under hypoxia conditions. The neuronal capacity of glycogen degradation is present in the in vivo situation, both in neurons from Drosophila melanogaster and from mice. The glycogen degradation machinery is mediated through the expression of glycogen phosphorylase (GP). Neurons express the brain isoform of the enzyme, but not the muscle, as astrocytes do. This isoform is present in neuronal cultures, as well as in neurons from adult mice brain slices. Hypoxia causes the dephosphorylation and activation of GS. GS actively synthesizes glycogen, although the global glycogen levels diminished in hypoxia. Indeed, an apparent futile cycle is taking place under hypoxia, where both synthesis and degradation are activated. Finally, we have demonstrated that glycogen metabolism is part of the protection machinery the neuron activates for tolerating the hypoxia conditions. Consequently, neurons without GS have a higher mortality rate that these who actively express the enzyme. In Drosophila melanogaster, flies with reduced GS levels specifically in neurons have an impaired phenotype in their reponse to hypoxic conditions. In conclusion, this thesis presents evidences that show neurons have an active glycogen metabolism which plays a key role in the neuronal response to hypoxia.

La diferenciació dels precursors neuronals en cèl·lules especialitzades implica una restricció de la seva capacitat proliferativa i la sortida definitiva del cicle cel·lular. Entre les proteïnes HLH activadores de la diferenciació hi ha les proteïnes E (E47, E12, HEB, E2-2), les quals s’expressen a la majoria de teixits. Al nostre laboratori es va descriure que la proteïna E47 forma heterodímers amb la proteïna HLH específica de teixit NeuroD, i activa l’expressió del receptor del BDNF (TrkB) i l’inhibidor de cicle p21CIP en resposta a la senyal diferenciadora d’àcid retinoic (RA). La correcta expressió del receptor TrkB juga un paper clau en el desenvolupament del sistema nerviós en vertebrats i la seva alteració s’ha relacionat amb diferents malalties humanes importants. En aquest treball s’ha demostrat que la quinasa MLK2 interacciona amb la bHLH E47 en cèl·lules de neuroblastoma SHSY-5Y. Es proposa que la MLK2 controla l’activitat del factor bHLH E47 a través de la seva fosforilació, la qual redueix l’activació del promotor de trkB. A més, la inhibició de la MLK2 augmenta l’expressió de l’mRNA de trkB in vivo explicant perquè aquesta inhibició no només prevé l’activació dels processos de mort cel·lular sinó que també ajuda a les vies de supervivència. D’altra banda, estudis molt recents revelen la importància dels processos de localització d’mRNAs als axons i a les dendrites i la seva traducció localitzada. Conèixer com es regula la localització dels mRNAs i la seva traducció localitzada a nivell molecular ajuda a entendre aspectes fonamentals de la plasticitat i la diferenciació neuronal. Durant el transport dels mRNAs, la seva traducció està reprimida i aquesta s’activa a llocs concrets com a resposta a senyals sinàptics, i en conseqüència, s’activa la plasticitat neuronal. Prèviament, al nostre laboratori, es va demostrar que la proteïna KIS pot estimular la traducció localitzada d’mRNAs, afavorir el creixement neurític i la supervivència neuronal. En aquest treball demostrem que la KIS interacciona amb proteïnes i mRNAs implicats en activitat sinàptica, els quals són transportats a través de partícules mRNP. La nostra hipòtesi és que quan el grànul transportat per KIF3A arriba al seu destí, diversos estímuls sinàptics possiblement indueixin l’activació de la quinasa Src, la qual fosforila la KIS, activant la traducció dels mRNAs transportats. / La diferenciación de precursores neuronales en células especializadas implica la restricción de su capacidad proliferativa y la salida definitiva del ciclo celular. Entre las proteínas HLH activadoras de la diferenciación están las proteínas E (E47, E12, HEB, E2-2) las cuales se expresan en la mayoría de los tejidos. En nuestro laboratorio se describió que la proteína E47 forma heterodímeros con la proteína HLH especifica de tejido, NeuroD, y activa la expresión del receptor de BDNF (TrkB) y el inhibidor de ciclo p21CIP en respuesta a la señal diferenciadora del ácido retinoico (RA). La correcta expresión del receptor TrkB juega un papel clave en el desarrollo del sistema nervioso en vertebrados y su alteración se ha relacionado con diferentes enfermedades humanas importantes. En este trabajo se ha demostrado que la quinasa MLK2 interacciona con la bHLH E47 en células de neuroblastoma SHSY-5Y. Se propone que MLK2 controla la actividad del factor bHLH E47 a través de su fosforilación, la cual reduce la activación del promotor de trkB. Además la inhibición de MLK2 aumenta la expresión del mRNA de trkB in vivo explicando por qué esta inhibición no sólo previene la activación de los procesos de muerte celular sino que también ayuda a las vías de supervivencia. Por otro lado, estudios muy recientes revelan la importancia de los procesos de localización de mRNAs en axones y dendritas y de su traducción localizada. Conocer cómo se regula la localización de los mRNAs y su traducción localizada a nivel molecular ayuda a entender aspectos fundamentales de la plasticidad y la diferenciación neuronal. Durante el transporte de los mRNAs su traducción está reprimida y ésta se activa en lugares concretos en respuesta a señales sinápticas resultando en la activación de la plasticidad neuronal. Previamente, en nuestro laboratorio, se demostró que la proteína KIS puede estimular la traducción localizada de mRNAs, favorecer el crecimiento neurítico y la supervivencia neuronal. En este trabajo demostramos que KIS interacciona con proteínas y mRNAs implicados en actividad sináptica, los cuales son transportados a través de partículas mRNPs. Nuestra hipótesis es que cuando el gránulo transportado por KIF3A llega a su destino, varios estímulos sinápticos posiblemente induzcan la activación de la quinasa Src la cual fosforila KIS, activando la traducción de los mRNAs transportados. / The differentiation of neuronal precursors in specialized cells induces an increase of a restriction of their proliferative capacity and a complete exit of the cell cycle. Among the HLH protein activators of differentiation the E protein family (E47, E12, HEB, E2-2) is expressed in most of the tissues. In our laboratory it has been described that in response to the differentiating signal of retinoic acid (RA), E47 heterodimerizes with the HLH protein tissue specific NeuroD which activates the expression of the receptor BDNF (TrkB) and the cell cycle p21CIP inhibitor. TrkB expression plays a key role in the nervous system development in vertebrates, and its alteration has been related with different types of important human diseases. In the present work we identified the kinase MLK2 as an E47-interaction protein in SHSY-5Y human neuroblastoma cells. We propose MLK2 as a controller of the BDNF receptor TrkB through the phosphorylation of bHLH transcription factor E47 which reduces the activation of trkB promoter. Furthermore, MLK2 inhibition increases trkB mRNA expression in vivo. These results could explain the reason why the inhibition of MLKs avoid the activation of cell death program and also increase the cell survival pathway being a key component of their neuroprotector potential. In the other hand, recent studies some recent work reveal the importance of mRNA localization in axons and dendrites and its local translation. Unraveling how mRNA localization and its translation are regulated at molecular level will help to understand basic processes of neuronal differentiation and plasticity. Translation is inhibited during mRNA transport, and is activated in specific synapses in response to synapse signals resulting from activation of neuronal plasticity. Previous work from our laboratory demonstrated that protein kinase KIS can stimulate the local translation of mRNAs, increase the neuritic outgrowth and the neural survival. In the present work we demonstrate that KIS can interact with transported granular proteins and mRNAs importants for the synaptic activity. Our hypothesis is that when the granule reaches his fate through KIF3A, some synaptic stimuli induce the activation of the kinase Src, which phosphorylates KIS, therefore activating the transported transcript.