Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Sept. 22, 2008). Includes bibliographical references.

Thesis (Ph.D. in Neuroscience) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 84-93). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 74-84).

Thesis (Ph. D.)--University of Wisconsin, 1951. / Typescript (carbon copy). eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves [82]-86).

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 78-82).

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 79-82).

No description available.

Le cerveau antérieur est l’aire cérébrale supportant les fonctions biologiques les plus complexes. Certaines altérations de son développement peuvent entraîner des maladies psychiatriques comme l’autisme ou encore la schizophrénie. Ainsi, les cellules du cerveau, appelées neurones, doivent être correctement positionnés au sein du cerveau et établir des connexions (appelées synapses) avec les autres neurones. Ce travail de thèse vise à mieux comprendre comment le positionnement des neurones et la formation des synapses sont régulés dans le cerveau antérieur. En premier lieu, nous avons étudié l’impact de l’activité neuronale sur le positionnement des différents types de neurones du bulbe olfactif. Dans un second temps, nous avons identifié le gène NeuroD2 comme régulateur majeur de la formation synaptique dans le cortex, l’absence de ce gène dans le cortex provoquant également l’altération du comportement social des souris. / The forebrain is the brain area that supports the most complex biological functions. Any alteration during its development can provoke psychiatric disorders such as autism or schizophrenia. The cells composing the brain, called neurons, must be adequately positioned and must establish functional connections (named synapses) with other neurons. This thesis work aims at understanding how neuronal positioning and synapse formation are controlled in the forebrain. In a first instance, we explored the impact of neuronal activity on the positioning of the different subtypes of olfactory bulb neurons. In a second instance, we identified the gene NeuroD2 as a major regulator of synapse formation in the cortex, the absence of this gene leading to social behavior deficits as well.

Pregnenolone (PREG), the precursor of all neurosteroids, is synthesized in the nervous system from cholesterol and recent clinical studies indicate that reduced cognitive symptoms of schizophrenia correlate with elevated serum levels of pregnenolone sulfate (PregS), its immediate sulfated metabolite. PregS fulfills most of the classical criteria for an endogenous modulator of excitatory synaptic transmission, including: presence in nervous tissue at physiologically relevant concentrations, potentiation of N-methyl-D-aspartate receptor (NMDAR) mediated synaptic activity, and a mechanism for its inactivation. As NMDAR hypoactivity has been implicated in the pathophysiology of schizophrenia, defects in neurosteroid metabolism might play a role in its associated cognitive dysfunction. PregS improves memory performance in rodents and augments long-term potentiation (LTP), an electrophysiological correlate of synaptic plasticity that is stabilized by phosphorylation of the cAMP response element binding protein (CREB). We have previously demonstrated that PregS at low picomolar (pM) concentrations increases intracellular Ca2+ and CREB via synaptic NMDARs. Therefore, we hypothesized that low pM concentrations of PregS might potentiate spontaneous excitatory postsynaptic currents (sEPSCs) and promote molecular events underlying synaptic plasticity. Here, using whole-cell patch clamp recordings, we report that PregS enhances the frequency of sEPSCs of cultured hippocampal neurons by about 2-fold while not altering their amplitude or passive membrane properties. This suggests that PregS acts presynaptically by increasing the frequency of neurotransmitter release or postsynaptically by activating silent synapses. We then investigated the hypothesis that PregS increases α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and NMDAR subtypes at synapses as a molecular switch for this enhancement. We measured receptor redistribution and phosphorylation using fluorescence imaging and Western blot technology. The results demonstrate that PregS (50pM, 10min): (1) Increases AMPAR (GluA1)/PSD95 colocalization (dependent on L-type voltage-gated Ca+2 channel and synaptic NMDAR activity), and increases phosphorylation of GluA1 at serine-831/845; (2) Increases casein kinase 2 (CK2) dependent surface NMDAR2A (GluN2A) but not GluN1 or GluN2B; and (3) Increases GluN2B serine-1480 phosphorylation. The results show that PregS increases the frequency of excitatory synaptic transmission and increases surface/synaptic AMPARs and surface GluN2A (but not GluN1 or GluN2B) NMDARs, shifting the molecular composition of young glutamatergic synapses toward the adult GluN2A enriched synaptic phenotype.