70 research outputs found
Mechanisms of Synapse Assembly and Disassembly
AbstractThe mechanisms that govern synapse formation and elimination are fundamental to our understanding of neural development and plasticity. The wiring of neural circuitry requires that vast numbers of synapses be formed in a relatively short time. The subsequent refinement of neural circuitry involves the formation of additional synapses coincident with the disassembly of previously functional synapses. There is increasing evidence that activity-dependent plasticity also involves the formation and disassembly of synapses. While we are gaining insight into the mechanisms of both synapse assembly and disassembly, we understand very little about how these phenomena are related to each other and how they might be coordinately controlled to achieve the precise patterns of synaptic connectivity in the nervous system. Here, we review our current understanding of both synapse assembly and disassembly in an effort to unravel the relationship between these fundamental developmental processes
How Staying Negative Is Good for the (Adult) Brain: Maintaining Chloride Homeostasis and the GABA-Shift in Neurological Disorders
Excitatory-inhibitory (E-I) imbalance has been shown to contribute to the pathogenesis of a wide range of neurodevelopmental disorders including autism spectrum disorders, epilepsy, and schizophrenia. GABA neurotransmission, the principal inhibitory signal in the mature brain, is critically coupled to proper regulation of chloride homeostasis. During brain maturation, changes in the transport of chloride ions across neuronal cell membranes act to gradually change the majority of GABA signaling from excitatory to inhibitory for neuronal activation, and dysregulation of this GABA-shift likely contributes to multiple neurodevelopmental abnormalities that are associated with circuit dysfunction. Whilst traditionally viewed as a phenomenon which occurs during brain development, recent evidence suggests that this GABA-shift may also be involved in neuropsychiatric disorders due to the ādematurationā of affected neurons. In this review, we will discuss the cell signaling and regulatory mechanisms underlying the GABA-shift phenomenon in the context of the latest findings in the field, in particular the role of chloride cotransporters NKCC1 and KCC2, and furthermore how these regulatory processes are altered in neurodevelopmental and neuropsychiatric disorders. We will also explore the interactions between GABAergic interneurons and other cell types in the developing brain that may influence the GABA-shift. Finally, with a greater understanding of how the GABA-shift is altered in pathological conditions, we will briefly outline recent progress on targeting NKCC1 and KCC2 as a therapeutic strategy against neurodevelopmental and neuropsychiatric disorders associated with improper chloride homeostasis and GABA-shift abnormalities
Alternative Splicing of P/Q-Type Ca2+ Channels Shapes Presynaptic Plasticity
Alternative splicing of pre-mRNAs is prominent in the
mammalian brain, where it is thought to expand proteome
diversity. For example, alternative splicing of
voltage-gated Ca2+ channel (VGCC) a1 subunits can
generate thousands of isoforms with differential
properties and expression patterns. However, the
impact of this molecular diversity on brain function,
particularly on synaptic transmission, which crucially
depends on VGCCs, is unclear. Here, we investigate
how two major splice isoforms of P/Q-type VGCCs
(Cav2.1[EFa/b]) regulate presynaptic plasticity in
hippocampal neurons. We find that the efficacy of
P/Q-type VGCC isoforms in supporting synaptic
transmission is markedly different, with Cav2.1[EFa]
promoting synaptic depression and Cav2.1[EFb] synaptic
facilitation. Following a reduction in network
activity, hippocampal neurons upregulate selectively
Cav2.1[EFa], the isoform exhibiting the higher synaptic
efficacy, thus effectively supporting presynaptic
homeostatic plasticity. Therefore, the balance between
VGCC splice variants at the synapse is a key
factor in controlling neurotransmitter release and
presynaptic plasticity
Astrocyte GluN2C NMDA receptors control basal synaptic strengths of hippocampal CA1 pyramidal neurons in the stratum radiatum
Experience-dependent plasticity is a key feature of brain synapses for which neuronal N-Methyl-D-Aspartate receptors (NMDARs) play a major role, from developmental circuit refinement to learning and memory. Astrocytes also express NMDARs, although their exact function has remained controversial. Here, we identify in mouse hippocampus, a circuit function for GluN2C NMDAR, a subtype highly expressed in astrocytes, in layer-specific tuning of synaptic strengths in CA1 pyramidal neurons. Interfering with astrocyte NMDAR or GluN2C NMDAR activity reduces the range of presynaptic strength distribution specifically in the stratum radiatum inputs without an appreciable change in the mean presynaptic strength. Mathematical modeling shows that narrowing of the width of presynaptic release probability distribution compromises the expression of long-term synaptic plasticity. Our findings suggest a novel feedback signaling system that uses astrocyte GluN2C NMDARs to adjust basal synaptic weight distribution of Schaffer collateral inputs, which in turn impacts computations performed by the CA1 pyramidal neuron
Global Landscape of a Co-Expressed Gene Network in Barley and its Application to Gene Discovery in Triticeae Crops
Accumulated transcriptome data can be used to investigate regulatory networks of genes involved in various biological systems. Co-expression analysis data sets generated from comprehensively collected transcriptome data sets now represent efficient resources that are capable of facilitating the discovery of genes with closely correlated expression patterns. In order to construct a co-expression network for barley, we analyzed 45 publicly available experimental series, which are composed of 1,347 sets of GeneChip data for barley. On the basis of a gene-to-gene weighted correlation coefficient, we constructed a global barley co-expression network and classified it into clusters of subnetwork modules. The resulting clusters are candidates for functional regulatory modules in the barley transcriptome. To annotate each of the modules, we performed comparative annotation using genes in Arabidopsis and Brachypodium distachyon. On the basis of a comparative analysis between barley and two model species, we investigated functional properties from the representative distributions of the gene ontology (GO) terms. Modules putatively involved in drought stress response and cellulose biogenesis have been identified. These modules are discussed to demonstrate the effectiveness of the co-expression analysis. Furthermore, we applied the data set of co-expressed genes coupled with comparative analysis in attempts to discover potentially Triticeae-specific network modules. These results demonstrate that analysis of the co-expression network of the barley transcriptome together with comparative analysis should promote the process of gene discovery in barley. Furthermore, the insights obtained should be transferable to investigations of Triticeae plants. The associated data set generated in this analysis is publicly accessible at http://coexpression.psc.riken.jp/barley/
Cellular and molecular basis of synaptic strength regulation
Synapses mediate information transmission in the nervous system, and dynamic changes in the efficacy of synaptic transmission or synaptic strength, play a fundamental role in cognitive functions including emotion, computation, perception and learning and memory. Our research seeks to understand how individual synapses acquire a particular strength, and how the strength of individual synapses is dynamically modified by network activity and in relationship to other synapses sharing the network. To address these questions experimentally, we combine methods of molecular biology, cell biology, biochemistry, electrophysiology, fluorescence liveimaging, and electron microscopy. In order to unravel the molecular mechanisms that underlie these processes, we have focused our attention on coordinate regulation of synapse structure and function. Towards this end, we used a novel photoconductive stimulation technique that illustrated the coordination remodeling of pre and postsynaptic cytoskeleton during synaptic plasticity (Colicos et al., 2001). This motivated us to examine how synapse adhesion proteins that couple the pre and the postsynaptic terminals directly or via the extracellular matrix and glial cells contribute to synaptic strength regulation. In this lecture I will highlight the roles for integrins and N-cadherin/Ī²-catenin complex that we have identified in controlling glutamate receptors and homeostatic forms of synaptic plasticity (Okuda et al., 2007; Cingolani et al., 2008; Vitureira et al., 2011; Pozo et al., 2012; McGeachie et al., 2012). Reference
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