From Synapse to Nucleus: Calcium-Dependent Gene Transcription in the Control of Synapse Development and Function

Greer, Paul L.; Greenberg, Michael E.

doi:10.1016/j.neuron.2008.09.002

Cited by 586 publications

(590 citation statements)

References 159 publications

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“…Greenberg and colleagues [40-42] have demonstrated that specific activity-regulated transcription factors are involved in synapse elimination and inhibitory synapse formation. More recently, Bonni and colleagues [8] have specifically implicated NeuroD2 in a pathway regulating the differentiation of pre-synaptic terminals in the cerebellum.…”

Section: Discussionmentioning

confidence: 99%

“…The hippocampal MF synapse develops entirely during the postnatal period and thus during a period when an animal is exposed to a diverse set of environmental influences [9,10]. The long-term effects of such activity at the neuronal level are determined by calcium-regulated transcription [42]. As a calcium-dependent transcription factor, NeuroD2 may function as part of a regulatory pathway matching PSD95 expression to the level of synaptic activity seen by a particular neuron and thereby contribute to activity-dependent synaptic development.…”

Section: Discussionmentioning

confidence: 99%

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NeuroD2 regulates the development of hippocampal mossy fiber synapses

et al. 2012

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BackgroundThe assembly of neural circuits requires the concerted action of both genetically determined and activity-dependent mechanisms. Calcium-regulated transcription may link these processes, but the influence of specific transcription factors on the differentiation of synapse-specific properties is poorly understood. Here we characterize the influence of NeuroD2, a calcium-dependent transcription factor, in regulating the structural and functional maturation of the hippocampal mossy fiber (MF) synapse.ResultsUsing NeuroD2 null mice and in vivo lentivirus-mediated gene knockdown, we demonstrate a critical role for NeuroD2 in the formation of CA3 dendritic spines receiving MF inputs. We also use electrophysiological recordings from CA3 neurons while stimulating MF axons to show that NeuroD2 regulates the differentiation of functional properties at the MF synapse. Finally, we find that NeuroD2 regulates PSD95 expression in hippocampal neurons and that PSD95 loss of function in vivo reproduces CA3 neuron spine defects observed in NeuroD2 null mice.ConclusionThese experiments identify NeuroD2 as a key transcription factor that regulates the structural and functional differentiation of MF synapses in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NeuroD2 regulates the development of hippocampal mossy fiber synapses

et al. 2012

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“…[96][97][98] Activation of specific transmembrane channels increases the levels of Ca 2þ in the nucleus and the cytosol, including the cytosol's dendritic and axonal spaces. [99][100][101][102][103][104] Ca 2þ channels reside in the neuron's plasma membrane, particularly its synaptic regions, and also in intracellular membranes of the endoplasmic reticulum (ER), which is present in axons and dendrites as well. 96,97 The ER lumen is one site of Ca 2þ storage, in addition to extracellular space.…”

Section: The Fragment Generation Hypothesismentioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

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“…Des efforts considérables ont été dévolus à la compréhension des mécanismes de plasticité morphologique dans les contextes d'apprentissage et de rétention [23]. Ainsi, la plasticité structurale à court terme dépendrait de modifications post-traductionnelles de protéines associées au cytosquelette, alors que des changements persistants dépendraient également de processus transcriptionnels [24,25]. Si l'application locale in vivo de glucocorticoïdes par le biais d'une craniotomie augmente rapidement (< 20 minutes) la formation d'épines dendritiques, celle d'antagonistes du récepteur de glucocorticoïdes (GR) empêche cette formation.…”

Section: Des Mécanismes Rapides Facilitent La Formation Des éPines Deunclassified

Vers une explication des effets mnémoniques des glucocorticoïdes ?

Jeanneteau

2015

Med Sci (Paris)

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> Certains événements sont mieux mémorisés dans un contexte de stress. En effet, les mécanismes engagés par le stress facilitent la formation de la mémoire, mais ils peuvent aussi la détruire. C'est une des difficultés auxquelles se heurtent les stratégies d'identification de cibles médicamenteuses favorisant ou inhibant les effets mnémoniques des glucocorticoïdes. L'imagerie in vivo offre une vision nouvelle des bases structurales de la mémoire pendant les phases d'apprentissage et de la consolidation. La survie des traces de la mémoire dépend de la dose et du rythme d'exposition aux glucocorticoïdes. Ainsi, des rythmes biologiques de glucocorticoïdes anormalement haut ou bas peuvent endommager la plasticité des réseaux neuronaux nécessaires à la formation et à la consolidation de la mémoire. Ces découvertes offrent de nouvelles perspectives de travail pour mieux comprendre le développement de troubles mnésiques et de maladies neuropsychiatriques, telles que la dépression, qui se développent dans un contexte de stress. < glucocorticoïdes, dont la sécrétion est sensible au stress, causent un réarrangement réversible des réseaux de connectivité neuronale dans les régions du cerveau impliquées dans l'apprentissage de la récom-pense, de la cognition, des émotions, de la perception sensorielle [6,7]. Une hypothèse est que les glucocorticoïdes, bien qu'accessibles à tous les neurones du cerveau, modifieraient les réseaux neuronaux sensibles au contexte environnemental tout en préservant les autres [8,9]. Rares sont les preuves physiologiques directes d'une telle spé-cificité d'action. L'imagerie fonctionnelle in vivo, grâce au suivi longitudinal de la dynamique structurale des mêmes neurones au cours des changements de contextes qu'elle permet, valide l'hypothèse d'une coïncidence de détection entre les signalisations induites par les glucocorticoïdes et l'activité neuronale. Reste à déterminer si les traces de la mémoire (engrammes) (voir Glossaire) 1 s'établissent par l'intermédiaire de ce type de mécanisme. Les glucocorticoïdes augmentent le renouvellement des épines dendritiquesDes études classiques de comportement et d'électrophysiologie indiquent que les glucocorticoïdes ont des effets robustes, mais complexes, sur la plasticité synaptique, l'apprentissage et la mémoire [9]. Ces effets sont exprimés sous la forme caractéristique de courbe inversée, car seule une concentration optimale de glucocorticoïde, introduite au bon moment, produit une plasticité maximale. Des 1 Plusieurs définitions d'usage sont consultables dans le Glossaire.

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From Synapse to Nucleus: Calcium-Dependent Gene Transcription in the Control of Synapse Development and Function

Cited by 586 publications

References 159 publications

NeuroD2 regulates the development of hippocampal mossy fiber synapses

NeuroD2 regulates the development of hippocampal mossy fiber synapses

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Vers une explication des effets mnémoniques des glucocorticoïdes ?

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