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Carlos DOTTI ‘Survival and plasticity balance in the aged brain.’

Abstract :

Aging refers to the numerous changes that occur with time, consequence of the dysfunction and death of cells due to the build-up of stress by-products, activation of the aging genes and environmental insults.
Because neurons are among the most metabolically demanding cells of the organism, and therefore high stress generators, the stress by-product scavenging (anti-oxidant) mechanisms in the brain are weak yet neuronal death is insignificant in the aged individual, we hypothesized that brain cells ought to use non-conventional, robust, survival mechanisms. We found that one such mechanism is through the transcriptional regulation of the lipidic composition of the plasma membrane, more specifically the subtle but steady reduction in membrane cholesterol with a parallel increase in sphingomyelin. We corroborated that these changes are the consequence of metabolic stress due to excitatory neurotransmission and involve the activation, at the promoter level, of the gene 24 hydroxy-cholesterol (Cyp46A1). Gain and loss-of-function experiments confirmed that these lipid changes are critical for neuronal survival. However, a different consequences of the cholesterol/sphingomyelin change is a change in the lateral diffusion of membrane receptors, which we studied by single particle tracking. In short, glutamate receptors of the AMPA type become less mobile in the synapses of old animals upon the stimulation with glutamate agonists, in a cholesterol loss-dependent manner. This reduced mobility impacts on the capacity of neurons to “learn” (in electrical terms), indicating that increased survival and decreased performance are in-line phenomena, not in-parallel. In agreement, the lipid changes in the plasma membrane of old neurons underly the low activity of the synaptic plasticity mediator PLCg, leading to reduced PI(4,5)P2 hydrolysis and consequently less PKC-mediated activation of CREBS and synthesis of genes involved in learning and memory. Our data contribute to understand the mechanisms behind survival strength and functional decay of the brain during physiological aging, which we hope can be of use to understand the functional decay of pathological aging.

Selected publications

N-cadherin specifies first asymmetry in developing neuronsGärtner A, Fornasiero E, Munck S, Vennekens K, Seuntjens E, Huttner W, Valtorta F, Dotti CEMBO JOURNAL, e-pub, e-pub, 2012

Cytokinesis remnants define first neuronal asymmetry in vivoPollarolo G, Schulz J, Munck S, Dotti CNATURE NEUROSCIENCE, 14, 1525-33, 2011
Kidins220/ARMS modulates the activity of microtubule-regulating proteins and controls neuronal polarity and developmentHiguero A, Sanchez-Ruiloba L, Doglio L, Portillo F, Abad-Rodriguez J, Dotti C, Iglesias TJOURNAL OF BIOLOGICAL CHEMISTRY, 285, 1343-57, 2010

Cholesterol Loss Enhances TrkB Signaling in Hippocampal Neurons Aging in VitroMartin M, Perga S, Trovo L, Rasola A, Holm P, Rantamaki T, Harkany T, Castren E, Chiara F, Dotti CMOLECULAR BIOLOGY OF THE CELL, 19, 2101-2112, 2008

Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor-dependent mannerSchubert V, Da Silva J, Dotti CJOURNAL OF CELL BIOLOGY, 172, 453-67, 2006

Scientific focus :

One of the goals of our group is to unravel the basic mechanisms of neuronal polarization, i.e. the position of axon and dendrites in a neuron. This process starts with the migration of the last post-mitotic neuroblasts from the germinal layer to their final destination in the cortical layer, the generation of short cytoplasmic extensions serving as sensors for the extracellular environment and as a stop-signal to determine its final positioning. The accuracy of this process is of fundamental importance for proper neuronal connectivity.

To address this issue, we have largely relied on neuron differentiation experiments with rodent embryonic hippocampal neurons in vitro. The current project will study this process in an in situ environment using wild-type and genetically modified mice and Drosophila melanogaster.

Generation and maintenance of plasma membrane asymmetry is essential for proper cell function in any polarized cell, including neurons. In neurons, action potentials are produced by a peculiar molecular composition of the axonal membrane, whereas dendritic electronic potentials and growth factors’ uptake are determined by the segregated positioning of a series of specific receptors.....

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