Signaling from the Cytoplasm to the Nucleus in Striatal Medium-Sized Spiny Neurons

Striatal medium-sized spiny neurons (MSNs) receive massive glutamate inputs from the cerebral cortex and thalamus and are a major target of dopamine projections. Interaction between glutamate and dopamine signaling is crucial for the control of movement and reward-driven learning, and its alterations are implicated in several neuropsychiatric disorders including Parkinson’s disease and drug addiction. Long-lasting forms of synaptic plasticity are thought to depend on transcription of gene products that alter the structure and/or function of neurons. Although multiple signal transduction pathways regulate transcription, little is known about signal transmission between the cytoplasm and the nucleus of striatal neurons and its regulation. Here we review the current knowledge of the signaling cascades that target the nucleus of MSNs, most of which are activated by cAMP and/or Ca2+. We outline the mechanisms by which signals originating at the plasma membrane and amplified in the cytoplasm are relayed to the nucleus, through the regulation of several protein kinases and phosphatases and transport through the nuclear pore. We also summarize the identified mechanisms of transcription regulation and chromatin remodeling in MSNs that appear to be important for behavioral adaptations, and discuss their relationships with epigenetic regulation

MicroRNA networks surrounding APP and amyloid-β metabolism - implications for Alzheimer's disease

MicroRNAs (miRNAs) are small non-coding RNA regulators of protein synthesis that function as "fine-tuning" tools of gene expression in development and tissue homeostasis. Their profiles are significantly altered in neurodegenerative diseases such as Alzheimer's disease (AD) that is characterized by both amyloid-β (Aβ) and tau deposition in brain. A key challenge remains in determining how changes in miRNA profiles translate into biological function in a physiological and pathological context. The key lies in identifying specific target genes for deregulated miRNAs and understanding which pathogenic factors trigger their deregulation. Here we review the literature about the intricate network of miRNAs surrounding the regulation of the amyloid precursor protein (APP) from which Aβ is derived by proteolytic cleavage. Normal brain function is highly sensitive to any changes in APP metabolism and miRNAs function at several steps to ensure that the correct APP end product is produced and in the right form and abundance. Disruptions in this miRNA regulatory network may therefore alter Aβ production, which in turn can affect miRNA expression

A phosphatase cascade by which rewarding stimuli control nucleosomal response

ArticleInternational audienceDopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascad

Modes of Aβ toxicity in Alzheimer’s disease

Alzheimer’s disease (AD) is reaching epidemic proportions, yet a cure is not yet available. While the genetic causes of the rare familial inherited forms of AD are understood, the causes of the sporadic forms of the disease are not. Histopathologically, these two forms of AD are indistinguishable: they are characterized by amyloid-β (Aβ) peptide-containing amyloid plaques and tau-containing neurofibrillary tangles. In this review we compare AD to frontotemporal dementia (FTD), a subset of which is characterized by tau deposition in the absence of overt plaques. A host of transgenic animal AD models have been established through the expression of human proteins with pathogenic mutations previously identified in familial AD and FTD. Determining how these mutant proteins cause disease in vivo should contribute to an understanding of the causes of the more frequent sporadic forms. We discuss the insight transgenic animal models have provided into Aβ and tau toxicity, also with regards to mitochondrial function and the crucial role tau plays in mediating Aβ toxicity. We also discuss the role of miRNAs in mediating the toxic effects of the Aβ peptide

Neuronal activity-regulated gene transcription: how are distant synaptic signals conveyed to the nucleus?

Synaptic activity can trigger gene expression programs that are required for the stable change of neuronal properties, a process that is essential for learning and memory. Currently, it is still unclear how the stimulation of dendritic synapses can be coupled to transcription in the nucleus in a timely way given that large distances can separate these two cellular compartments. Although several mechanisms have been proposed to explain long distance communication between synapses and the nucleus, the possible co-existence of these models and their relevance in physiological conditions remain elusive. One model suggests that synaptic activation triggers the translocation to the nucleus of certain transcription regulators localised at postsynaptic sites that function as synapto-nuclear messengers. Alternatively, it has been hypothesised that synaptic activity initiates propagating regenerative intracellular calcium waves that spread through dendrites into the nucleus where nuclear transcription machinery is thereby regulated. It has also been postulated that membrane depolarisation of voltage-gated calcium channels on the somatic membrane is sufficient to increase intracellular calcium concentration and activate transcription without the need for transported signals from distant synapses. Here I provide a critical overview of the suggested mechanisms for coupling synaptic stimulation to transcription, the underlying assumptions behind them and their plausible physiological significance

Regulation of gene transcription by neuronal activity

<p><strong>Background</strong></p> <p>Synaptic activity can trigger gene expression programs that are required for the stable change of neuronal properties, a process that is essential for learning and memory. Currently, it is still unclear how the stimulation of dendritic synapses can be coupled to transcription in the nucleus in a timely way given that large distances can separate these two cellular compartments. Although several mechanisms have been proposed to explain long distance communication between synapses and the nucleus, the possible co-existence of these models and their relevance in physiological conditions remain elusive. In a review published on <em><strong>F1000Research</strong></em>, I provide a critical overview of the suggested mechanisms for coupling synaptic stimulation to transcription, the underlying assumptions behind them and their plausible physiological significance.</p> <p><strong>Image description</strong></p> <p>Confocal image of a mouse piriform cortex section stained with P-ERK1/2 antibodies. A 16 pseudo-color palette highlights the intensity of P-ERK1/2 fluorescence (blue is low; red is high). High P-ERK1/2 immunoreactivity is present in the nucleus of neurons in response to synaptic activity. Nuclear P-ERK1/2 participates in the regulation of gene transcription.</p

Differential nuclear architecture of striatal neuron populations

<p><strong>Background:</strong></p> <p>The striatum is composed by five different neuronal populations of which the MSNs constitute the major cell type (~95%). The remaining ~5% of the striatal neurons comprise aspiny interneurons, which have been classified on the basis of their morphology, protein content and electrophysiological properties as large cholinergic interneurons and somatostatin-, parvalbumin- and calretinin-expressing GABAergic interneurons. In addition to these discriminative features, we showed that nuclear morphology is also particular for each striatal cell type (Matamales/Bertran-Gonzalez et al., 2009). Indeed, the characteristic nuclear architecture of striatal populations is evident on DNA staining with TO-PRO-3, which reveals differences regarding the nuclear diameter, the nuclear shape and the pattern of heterochromatin distribution. Thus, nuclear staining with TO-PRO-3 provides a simple means for the identification of MSNs in the absence of other markers. In addition, the other striatal neurons also have distinct nuclear staining patterns, which allow a good prediction of their nature. This method may be useful to identify striatal neurons in tissue sections and potentially in living tissue, using vital DNA fluorescent dyes. With this simple method we carefully quantified striatal neuronal populations and we clearly showed that all MSNs express either D1R or D2R or both. It will be worth to test whether nuclear architecture in striatal neurons is linked to differences in rates of transcriptional activity. In addition, it will be interesting to analyze whether a correlation between the organization of the nucleus of striatal neurons and their characteristic neuronal activity exists.</p> <p> </p> <p><strong>Figure Legend: </strong></p> <p>(A-E) Schematic view of striatal neurons nuclear morphology: (A), MSNs; (B), Parvalbumin interneurons; (C), Calretinin interneurons; (D), Somatostatin interneurons; (E), Cholinergic interneurons. The three different features that allow the identification of striatal neuronal populations based on their nuclear architecture are represented: blue line designates nuclear shape; dashed green line and numbers indicate average nuclear diameter (μm); red dots are DNA chromocenters; red line represents heterochromatin rim. For details, see Matamales/Bertran-Gonzalez et al., 2009.</p

Signalisation au noyau dans neurones striatal (mécanismes de translocation de la DARPP-32)

La signalisation dopaminergique dans le striatum joue un rôle essentiel dans le contrôle des mouvements, la motivation, la formation des habitudes et la mémoire procédurale, et qui est impliqué dans des maladies neuropsychiatriques majeures comme la maladie de Parkinson et la toxicomanie. Notre étude identifie une voie de signalisation inédite par laquelle la dopamine induit une accumulation nucléaire de DARPP-32, une protéine clef de la signalisation dopaminergique, sous une forme capable d inhiber une importante phosphatase nucléaire, la PP1. Nous avons identifié les mécanismes par lequel DARPP-32 est capable de s accumuler dans le noyau est les facteurs qui régulent la translocation. Nous avons montré que cette accumulation contribue à la régulation de la phosphorylation de l histone H3, et vraisemblablement d'autres protéines nucléaires qui restent à identifier. L accumulation de cet inhibiteur de phosphatase dans le noyau pourrait ainsi participer à la plasticité neuronale requise pour les renforcements comportementaux en modulant l expression de gènes.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF