The neuronal monocarboxylate transporter MCT2: its regulation by BDNF and its role in learning and memory

Glucose has been considered the major, if not the exclusive, energy substrate for the brain. But under certain physiological and pathological conditions other substrates, namely monocarboxylates (lactate, pyruvate and ketone bodies), can contribute significantly to satisfy brain energy demands. These monocarboxylates need to be transported across the blood-brain barrier or out of astrocytes into the extracellular space and taken up into neurons. It has been shown that monocarboxylates are transported by a family of proton-linked transporters called monocarboxylate transporters (MCTs). In the central nervous system, MCT2 is the predominant neuronal isoform and little is known about the regulation of its expression. Noradrenaline (NA), insulin and IGF-1 were previously shown to enhance the expression of MCT2 in cultured cortical neurons via a translational mechanism. Here we demonstrate that the well known brain neurotrophic factor BDNF enhances MCT2 protein expression in cultured cortical neurons and in synaptoneurosome preparations in a time- and concentrationdependent manner without affecting MCT2 mRNA levels. We observed that BDNF induced MCT2 expression by activation of MAPK as well as PI3K/Akt/mTOR signaling pathways. Furthermore, we investigated the possible post-transcriptional regulation of MCT2 expression by a neuronal miRNA. Then, we demonstrated that BDNF enhanced MCT2 expression in the hippocampus in vivo, in parallel with some post-synaptic proteins such as PSD95 and AMPA receptor GluR2/3 subunits, and two immediate early genes Arc and Zif268 known to be expressed in conditions related to synaptic plasticity. In the last part, we demonstrated in vivo that a downregulation of hippocampal MCT2 via silencing with an appropriate lentiviral vector in mice caused an impairment of working memory without reference memory deficit. In conclusion, these results suggest that regulation of neuronal monocarboxylate transporter MCT2 expression could be a key event in the context of synaptic plasticity, allowing an adequate energy substrate supply in situations of altered synaptic efficacy. - Le glucose représente le substrat énergétique majeur pour le cerveau. Cependant, dans certaines conditions physiologiques ou pathologiques, le cerveau a la capacité d'utiliser des substrats énergéiques appartenant à la classe des monocarboxylates (lactate, pyruvate et corps cétoniques) afin de satisfaire ses besoins énergétiques. Ces monocarboxylates doivent être transportés à travers la barrière hématoencéphalique mais aussi hors des astrocytes vers l'espace extracellulaire puis re-captés par les neurones. Leur transport est assuré par une famillle de transporteurs aux monocarboxylates (MCTs). Dans le système nerveux central, les neurones expriment principalement l'isoforme MCT2 mais peu d'informations sont disponibles concernant la régulation de son expression. Il a été montré que la noradrénaline, l'insuline et l'IGF-1 induisent l'expression de MCT2 dans des cultures de neurones corticaux par un mécanisme traductionnel. Dans cette étude nous démontrons dans un premier temps que le facteur neurotrophique BDNF augmente l'expression de MCT2 à la fois dans des cultures de neurones corticaux et dans les préparations synaptoneurosomales selon un décours temporel et une gamme de concentrations propre. Aucun changement n'a été observé concernant les niveaux d'ARNm de MCT2. Nous avons observé que le BDNF induisait l'expression de MCT2 par l'activation simultanée des voies de signalisation MAPK et PI3K/Akt/mTOR. De plus, nous nous sommes intéressés à une potentielle régulation par les micro-ARNs de la synthèse de MCT2. Ensuite, nous avons démontré que le BDNF induit aussi l'expression de MCT2 dans l'hippocampe de la souris en parallèle avec d'autres protéines post-synaptiques telles que PSD95 et GluR2/3 et avec deux « immediate early genes » tels que Arc et Zif268 connus pour être exprimés dans des conditions de plasticité synaptique. Dans un dernier temps, nous avons démontré qu'une diminution d'expression de MCT2 induite par le biais d'un siRNA exprimé via un vecteur lentiviral dans l'hippocampe de souris générait des déficits de mémoire de travail sans affecter la mémoire de référence. En conclusion, ces résultats nous suggèrent que le transporteur aux monocarboxylates neuronal MCT2 serait essentiel pour l'apport énergétique du lactate pour les neurones dans des conditions de haute activité neuronale comme c'est le cas pendant les processus de plasticité synaptique.

Possible roles of COX-1 in learning and memory impairment induced by traumatic brain injury in mice

People who suffer from traumatic brain injury (TBI) often experience cognitive deficits in spatial reference and working memory. The possible roles of cyclooxygenase-1 (COX-1) in learning and memory impairment in mice with TBI are far from well known. Adult mice subjected to TBI were treated with the COX-1 selective inhibitor SC560. Performance in the open field and on the beam walk was then used to assess motor and behavioral function 1, 3, 7, 14, and 21 days following injury. Acquisition of spatial learning and memory retention was assessed using the Morris water maze on day 15 post-TBI. The expressions of COX-1, prostaglandin E2 (PGE2), interleukin (IL)-6, brain-derived neurotrophic factor (BDNF), platelet-derived growth factor BB (PDGF-BB), synapsin-I, and synaptophysin were detected in TBI mice. Administration of SC560 improved performance of beam walk tasks as well as spatial learning and memory after TBI. SC560 also reduced expressions of inflammatory markers IL-6 and PGE2, and reversed the expressions of COX-1, BDNF, PDGF-BB, synapsin-I, and synaptophysin in TBI mice. The present findings demonstrated that COX-1 might play an important role in cognitive deficits after TBI and that selective COX-1 inhibition should be further investigated as a potential therapeutic approach for TBI.

EdShare: Sharing for learning and teaching

A powerpoint presentation given by Hugh Davis and Debra Morris at the University of Southampton Learning and Teaching Week event 2 April 2008.

Learning and teaching with maps.

El rápido crecimiento de mapas en internet, atlas digitales y Sistemas de Información Geográfica (SIG) exige nuevas habilidades, junto con las tradicionales como la localización de lugares utilizando un mapa. Este recurso explica a los niños y a los jóvenes cómo leer, comprender e interpretar los mapas y a los profesores la manera más eficaz de enseñar con los mapas. Presta especial atención a la forma de aprendizaje con este material que puede contribuir al desarrollo cognitivo y a desarrollar habilidades en aritmética. Describe cómo los profesores pueden planificar un programa de estudios y sugiere actividades para los alumnos desde la escuela primaria a la secundaria. Incluye todos los aspectos del uso de mapas, que abarca todas las modalidades, incluidas los globos y atlas. El texto está ampliamente ilustrado con ejemplos, incluyendo los mapas realizados por los propios niños con materiales convencionales, así como programas informáticos. Una característica particular de este recurso es la integración de mapas digitales y convencionales, de internet adecuados a las necesidades de educación primaria y secundaria. Tiene apéndice con web de organizaciones y recursos citados en el texto, bibliografía e índice alfabético.

The digital classroom : harnessing technology for the future of learning and teaching.

Basado en el Proyecto Interactivo de investigación, este libro examina e ilustra cómo las tecnologías digitales pueden transformar el aprendizaje a través del currículo. Al observar los distintos entornos educativos en los que se mueven los niños y jóvenes-la casa y la escuela en las etapas primaria y secundaria-los profesionales piensan en que las nuevas tecnologías (TIC) suponen una ayuda para planificar y apoyar un aprendizaje eficaz en las clases. También, se ofrece a los lectores, a través de ejercicios prácticos y temas para la reflexión, la oportunidad de examinar su propia práctica docente y su experiencia en relación con estas tecnologías y entender sus beneficios y limitaciones.

Unlocking learning and teaching with ICT : identifying and overcoming barriers.

En primer lugar, identifica las barreras que aún existen para la integración con éxito de las tecnologías de la información y la comunicación (TIC) en las escuelas, así como propone métodos y estrategias para su superación. También, muestra cómo la utilización de estas tecnologías ayuda a los niños a aprender y a mejorar sus capacidades.

Learning and teaching using digital books : opportunities and constraints

Resumen basado en el de la publicaci??n

More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory.

Decades of research on the cellular mechanisms of memory have led to the widely held view that memories are stored as modifications of synaptic strength. These changes involve presynaptic processes, such as direct modulation of the release machinery, or postsynaptic processes, such as modulation of receptor properties. Parallel studies have revealed that memories might also be stored by nonsynaptic processes, such as modulation of voltage-dependent membrane conductances, which are expressed as changes in neuronal excitability. Although in some cases nonsynaptic changes can function as part of the engram itself, they might also serve as mechanisms through which a neural circuit is set to a permissive state to facilitate synaptic modifications that are necessary for memory storage.

Casting materials and their application in research and teaching

From a biological point of view, casting refers to filling of anatomical and/or pathological spaces with extraneous material that reproduces a three-dimensional replica of the space. Casting may be accompanied by additional procedures such as corrosion, in which the soft tissue is digested out, leaving a clean cast, or the material may be mixed with radiopaque substances to allow x-ray photography or micro computed topography (µCT) scanning. Alternatively, clearing of the surrounding soft tissue increases transparency and allows visualization of the casted cavities. Combination of casting with tissue fixation allows anatomical dissection and didactic surgical procedures on the tissue. Casting materials fall into three categories namely, aqueous substances (India ink, Prussian blue ink), pliable materials (gelatins, latex, and silicone rubber), or hard materials (methyl methacrylates, polyurethanes, polyesters, and epoxy resins). Casting has proved invaluable in both teaching and research and many phenomenal biological processes have been discovered through casting. The choice of a particular material depends inter alia on the targeted use and the intended subsequent investigative procedures, such as dissection, microscopy, or µCT. The casting material needs to be pliable where anatomical and surgical manipulations are intended, and capillary-passable for ultrastructural investigations.

Industry Professionals Who Attain Leadership in Energy and Environmental Design (LEED) Accreditation: An Examination of Motivations in Human Resource (HR) Training and Development

Despite the economy, the green building industry continues to grow and drive the demand for environmentally conscious, highly skilled professionals (USGBC 2009). LEED Accredited Professionals (APs) have the knowledge and skills to meet such demand; however, information is limited regarding LEED APs or their motivations and expectations toward prospective employers. The author surveyed a sample of LEED Accredited architects and found a combination of job and personal factors motivated them to attain accreditation. LEED APs value both a competitive salary and commitment to sustainability in prospective employers. To attract, retain, and utilize LEED APs, executives in this industry must reexamine corporate culture, their willingness to pay for credentialing, and the alignment of their reputation with the desires of potential applicants.

The psychology of religion, and its application in preaching and teaching,

"Bibliographical note": p. 379-381.