MicroRNAs are small, non-coding RNAs that control the translation of target messenger RNAs, thereby regulating critical aspects of plant and animal development. In the mammalian nervous system, the ...spatiotemporal control of mRNA translation has an important role in synaptic development and plasticity. Although a number of microRNAs have been isolated from the mammalian brain, neither the specific microRNAs that regulate synapse function nor their target mRNAs have been identified. Here we show that a brain-specific microRNA, miR-134, is localized to the synapto-dendritic compartment of rat hippocampal neurons and negatively regulates the size of dendritic spines--postsynaptic sites of excitatory synaptic transmission. This effect is mediated by miR-134 inhibition of the translation of an mRNA encoding a protein kinase, Limk1, that controls spine development. Exposure of neurons to extracellular stimuli such as brain-derived neurotrophic factor relieves miR-134 inhibition of Limk1 translation and in this way may contribute to synaptic development, maturation and/or plasticity.
microRNAs, small non-coding RNAs that regulate gene expression at the post-transcriptional level, are emerging as important regulatory molecules involved in the fine-tuning of gene expression during ...neuronal development and function. microRNAs have roles during neuronal stem cell commitment and early differentiation as well as in later stages of neuronal development, such as dendritogenesis and synaptic plasticity. A link between microRNAs and neurological diseases, such as neurodegeneration or synaptic dysfunction, is becoming increasingly clear. This review summarizes the current knowledge of the function of microRNAs in the developing and adult nervous system and their potential contribution to the etiology of neurological diseases.
Abstract Due to the complex architecture of the brain, the precise regulation of the numerous genes and signalling molecules involved is paramount. A recently identified class of master regulatory ...molecules, known as microRNAs (miRNAs), have the potential to assist in the countless regulatory mechanisms that occur in the brain during neuronal development and function. In the process, these molecules have gained the ability to provide a very pervasive and potent layer of genetic control. MiRNAs, in general, are genome encoded, short, non-protein coding RNA molecules that are involved in gene regulation by targeting for translational repression and/or degradation large numbers of mRNA molecules simultaneously. While the brain is replete with miRNAs, their particular role(s) in the developmental and functional programs of neurons is just emerging. Additionally, dysfunction of these molecules may also contribute to the etiology of several neurodegenerative conditions. Therefore, the central aim of this review is to highlight recent findings in the field of miRNAs in neuronal development, function and dysfunction.
Local regulation of mRNA translation plays an important role in axon guidance, synaptic development, and neuronal plasticity. Little is known, however, regarding the mechanisms that control ...translation in neurons, and only a few mRNAs have been identified that are locally translated within axon and dendrites. Using Affymetrix gene arrays to identify mRNAs that are newly associated with polysomes after exposure to BDNF, we identified subsets of mRNAs for which translation is enhanced in neurons at different developmental stages. In mature neurons, many of these mRNAs encode proteins that are known to function at synapses, including CamKIIalpha, NMDA receptor subunits, and the postsynaptic density (PSD) scaffolding protein Homer2. BDNF regulates the translation of Homer2 locally in the synaptodendritic compartment by activating translational initiation via a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway. These findings suggest that BDNF likely regulates synaptic function by inducing the local synthesis of numerous synaptic proteins. The local translation of the cytoskeleton-associated protein Homer2 in particular might have important implications for growth cone dynamics and dendritic spine development.
The microRNA pathway has been implicated in the regulation of synaptic protein synthesis and ultimately in dendritic spine morphogenesis, a phenomenon associated with long-lasting forms of memory. ...However, the particular microRNAs (miRNAs) involved are largely unknown. Here we identify specific miRNAs that function at synapses to control dendritic spine structure by performing a functional screen. One of the identified miRNAs, miR-138, is highly enriched in the brain, localized within dendrites and negatively regulates the size of dendritic spines in rat hippocampal neurons. miR-138 controls the expression of acyl protein thioesterase 1 (APT1), an enzyme regulating the palmitoylation status of proteins that are known to function at the synapse, including the alpha(13) subunits of G proteins (Galpha(13)). RNA-interference-mediated knockdown of APT1 and the expression of membrane-localized Galpha(13) both suppress spine enlargement caused by inhibition of miR-138, suggesting that APT1-regulated depalmitoylation of Galpha(13) might be an important downstream event of miR-138 function. Our results uncover a previously unknown miRNA-dependent mechanism in neurons and demonstrate a previously unrecognized complexity of miRNA-dependent control of dendritic spine morphogenesis.
Affective disorders such as major depression and bipolar disorder are among the most prevalent forms of mental illness and their etiologies involve complex interactions between genetic and ...environmental risk factors. Over the past ten years, several genome wide association studies (GWAS) have identified
as one of the strongest genetic risk factors for the development of affective disorders. However, its role in disease pathogenesis is still largely unknown. Vulnerability to affective disorders also involves diverse environmental risk factors such as perinatal insults, childhood maltreatment, and other adverse pathophysiological or psychosocial life events. At the cellular level, such environmental influences may activate oxidative stress pathways, thereby altering neuronal plasticity and function. Mitochondria are the key organelles of energy metabolism and, further, highly important for the adaptation to oxidative stress. Accordingly, multiple lines of evidence including post-mortem brain and neuro-imaging studies suggest that psychiatric disorders are accompanied by mitochondrial dysfunction. In this study, we investigated the effects of
downregulation in combination with glutamate-induced oxidative stress on mitochondrial function, Ca
homeostasis, and cell viability in mouse hippocampal HT22 cells. We found that the siRNA-mediated knockdown of
preserved mitochondrial morphology, mitochondrial membrane potential, and ATP levels after glutamate treatment. Further,
silencing inhibited excessive mitochondrial reactive oxygen species formation and calcium influx, and protected the HT22 cells from oxidative cell death. Overall, our findings suggest that the GWAS-confirmed psychiatric risk gene
plays a major role in oxidative stress pathways with particular impact on mitochondrial integrity and function.
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