Post-transcriptional control of gene expression by microRNAs provides an important regulatory sys... more Post-transcriptional control of gene expression by microRNAs provides an important regulatory system within neurons, allowing co-ordinate and fine-tuned expression of plasticity-related proteins. Indeed, specific microRNAs have been shown to be regulated by synaptic activity in the dentate gyrus, and contribute to the regulated gene expression that underlies the persistence of long-term potentiation (LTP), a model of memory. To fully explore the contribution of microRNAs in synaptic plasticity, it is important to characterize the complete microRNA transcriptome in regions such as the dentate gyrus. Accordingly we used deep sequencing and miRDeep* analysis to search for novel microRNAs expressed in the dentate gyrus granule cell layer. Drawing on combined sequencing and bioinformatics analyses, including hairpin stability and patterns of precursor microRNA processing, we identified nine putative novel microRNAs. We did not find evidence of differential expression of any of these putative microRNAs following LTP at perforant path-granule cell synapses in awake rats (5h post-tetanus; p>0.05). Focusing on novel_miR-1, the most abundant novel miRNA, we showed that this sequence could be amplified from RNA extracted from dentate gyrus granule cells by reverse transcription-quantitative polymerase chain reaction. Further, by computationally predicting mRNA targets of this microRNA, we found that this novel microRNA likely contributes to the regulation of proteins that function at synapses.
Pathological accumulation of tau protein in brain cells is the hallmark of a group of neurodegene... more Pathological accumulation of tau protein in brain cells is the hallmark of a group of neurodegenerative diseases called tauopathies. Accumulation of tau protein begins years before the onset of symptoms, which include deficits in cognition, behaviour and movement. The pre-symptomatic phase of tauopathy may be the best time to deliver disease-modifying treatments, but this is only possible if prognostic, pre-symptomatic biomarkers are identified. Here we describe the profiling of blood plasma microRNAs in a mouse model of tauopathy, in order to identify biomarkers of pre-symptomatic tauopathy. Circulating RNAs were isolated from blood plasma of 16-week-old and 53-week-old hTau mice and age-matched wild type controls (n = 28). Global microRNA profiling was performed using small RNA sequencing (Illumina) and selected microRNAs were validated using individual TaqMan RT-qPCR. The area under the receiver operating characteristic curve (AUC) was used to evaluate discriminative accuracy. We identified three microRNAs (miR-150-5p, miR-155-5p, miR-375-3p) that were down-regulated in 16-week-old hTau mice, which do not yet exhibit a behavioural phenotype and therefore represent pre-symptomatic tauopathy. The discriminative accuracy was AUC 0.98, 0.95 and 1, respectively. Downregulation of these microRNAs persisted at 53 weeks of age, when hTau mice exhibit cognitive deficits and advanced neuropathology. Bioinformatic analysis showed that these three microRNAs converge on pathways associated with neuronal signalling and phosphorylation of tau. Thus, these circulating microRNAs appear to reflect neuropathological change and are promising candidates in the development of biomarkers of pre-symptomatic tauopathy.
Astrocytes actively regulate numerous cell types both within and outside of the central nervous s... more Astrocytes actively regulate numerous cell types both within and outside of the central nervous system in health and disease. Indeed, astrocyte morphology, gene expression and function, alongside the content of astrocyte-derived extracellular vesicles (ADEVs), is significantly altered by ageing, inflammatory processes and in neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Here, we review the relevant emerging literature focussed on perturbation in expression of microRNA (miRNA), small non-coding RNAs that potently regulate gene expression. Synthesis of this literature shows that ageing-related processes, neurodegenerative disease-associated mutations or peptides and cytokines induce dysregulated expression of miRNA in astrocytes and in some cases can lead to selective incorporation of miRNA into ADEVs. Analysis of the miRNA targets shows that the resulting downstream consequences of alterations to levels of miRNA includ...
The 2012 International Joint Conference on Neural Networks (IJCNN), 2012
Long-term potentiation (LTP) is a long-lasting enhancement in signal transmission between two neu... more Long-term potentiation (LTP) is a long-lasting enhancement in signal transmission between two neurons, and represents a widely accepted experimental model for long-term memory processes. Although it is now clear that the maintenance of LTP requires new gene transcription, little is known on the genetic mechanisms underlying these changes. We assume that an LTP-related gene regulatory network has two equilibrium states in terms of gene expression levels which correspond to a pre-and post-LTP states. This network is shifted from the first to the latter by means of a perturbation, which experimentally corresponds to the high-frequency stimulus necessary to induce LTP in vivo. Based on this assumption and by means of modeling the transcriptional regulation with weight matrices, we study the properties of the main LTP-related network recently proposed in [1]. First, we classify the LTP-related genes according to their relevance to the bistable dynamic output of the network. In addition, we demonstrate how the LTP gene regulatory network architecture holds a higher tendency towards bistable behaviours than we should expect of a random network.
Current clinical tests for Parkinson’s disease (PD) provide insufficient diagnostic accuracy lead... more Current clinical tests for Parkinson’s disease (PD) provide insufficient diagnostic accuracy leading to an urgent need for improved diagnostic biomarkers. As microRNAs (miRNAs) are promising biomarkers of various diseases, including PD, this systematic review and meta-analysis aimed to assess the diagnostic accuracy of biofluid miRNAs in PD. All studies reporting data on miRNAs expression in PD patients compared to controls were included. Gene targets and significant pathways associated with miRNAs expressed in more than 3 biofluid studies with the same direction of change were analyzed using target prediction and enrichment analysis. A bivariate model was used to calculate sensitivity, specificity, likelihood ratios, and diagnostic odds ratio. While miR-24-3p and miR-214-3p were the most reported miRNA (7 each), miR-331-5p was found to be consistently up regulated in 4 different biofluids. Importantly, miR-19b-3p, miR-24-3p, miR-146a-5p, and miR-221-3p were reported in multiple stu...
RNA sequencing offers unprecedented access to the transcriptome. Key to this is the identificatio... more RNA sequencing offers unprecedented access to the transcriptome. Key to this is the identification and quantification of many different species of RNA from the same sample at the same time. In this study we describe a novel protocol for simultaneous detection of coding and non-coding transcripts using modifications to the Ion Total RNA-Seq kit v2 protocol, with integration of QIASeq FastSelect rRNA removal kit. We report highly consistent sequencing libraries can be produced from both frozen high integrity mouse hippocampal tissue and the more challenging post-mortem human tissue. Removal of rRNA using FastSelect was extremely efficient, resulting in less than 1.5% rRNA content in the final library. We identified > 30,000 unique transcripts from all samples, including protein-coding genes and many species of non-coding RNA, in biologically-relevant proportions. Furthermore, the normalized sequencing read count for select genes significantly negatively correlated with Ct values fr...
RNA sequencing offers unprecedented access to the transcriptome. Key to this is the identificatio... more RNA sequencing offers unprecedented access to the transcriptome. Key to this is the identification and quantification of many different species of RNA from the same sample at the same time. In this study we describe a novel protocol for simultaneous detection of coding and non-coding transcripts using modifications to the Ion Total RNA-Seq kit v2 protocol, with integration of QIASeq FastSelect rRNA removal kit. We report highly consistent sequencing libraries can be produced from both frozen high integrity mouse hippocampal tissue and the more challenging post-mortem human tissue. Removal of rRNA using FastSelect was highly efficient, resulting in less than 1.5% rRNA content in the final library, significantly better than other reported rRNA removal techniques. We identified >30,000 unique transcripts from all samples, including protein-coding genes and many unique species of non-coding RNA, in biologically-relevant proportions. Furthermore, normalized sequencing read count for s...
Secreted amyloid precursor protein-alpha (sAPPα) has growth factor-like properties and can modula... more Secreted amyloid precursor protein-alpha (sAPPα) has growth factor-like properties and can modulate long-term potentiation (LTP) and memory. Here, we demonstrate that exposure to sAPPα converts short-lasting LTP into protein-synthesis-dependent late LTP in hippocampal slices from male rats. sAPPβ had no discernable effect. We hypothesized that sAPPα facilitated LTP via regulated glutamate receptor trafficking andde novoprotein synthesis. We found using a linear mixed model that sAPPα stimulated trafficking of GluA2-lacking AMPARs, as well as NMDARs to the extrasynaptic cell surface, in a calcium/calmodulin-dependent kinase II and protein kinase G-dependent manner. Both cell surface receptor accumulation and LTP facilitation were present even after sAPPα washout and inhibition of receptor trafficking or protein synthesis prevented all these effects. Direct visualization of newly synthesized proteins (FUNCAT-PLA) confirmed the ability of sAPPα to stimulatede novoprotein synthesis and ...
The persistence and input specificity of long-term potentiation (LTP) make it attractive as a mec... more The persistence and input specificity of long-term potentiation (LTP) make it attractive as a mechanism of information storage. In its initial phase, both in vivo and in vitro studies have shown that LTP is associated with increased membrane localization of AMPA receptor subunits, but the molecular basis of LTP maintenance over the long-term is still unclear. We have previously shown that expression of AMPA and NMDA receptor subunits is elevated in whole homogenates prepared from dentate gyrus 48 h after LTP induction in vivo. In the present study, we utilized laser microdissection (LMD) techniques to determine whether AMPA and NMDA receptor upregulation occurs specifically in the stimulated regions of the dentate gyrus dendritic arbor. Receptor proteins GluN1, GluA1 and GluA2, as well as postsynaptic density protein of 95 kDa and tubulin were detected by Western blot analysis in microdissected samples. Gradients of expression were observed for GluN1 and GluA2, decreasing from the inner to the outer zones of the molecular layer, and were independent of LTP. When induced at medial perforant path synapses, LTP was associated with an apparent specific redistribution of GluA1 and GluN1 to the middle molecular layer that contains these synapses. These data indicate that glutamate receptor proteins are delivered specifically to dendritic regions possessing LTP-expressing synapses, and that these changes are preserved for at least 48 h.
How memories are maintained, and how memories are lost during aging or disease, are intensely inv... more How memories are maintained, and how memories are lost during aging or disease, are intensely investigated issues. Arguably, the reigning theory is that synaptic modifications allow for the formation of engrams during learning, and sustaining engrams sustains memory. Activity-regulated gene expression profiles have been shown to be critical to these processes, and their control by the epigenome has begun to be investigated in earnest. Here, we propose a novel theory as to how engrams are sustained. We propose that many of the genes that are currently believed to underlie long-term memory are actually part of a "plasticity transcriptome" that underpins structural and functional modifications to neuronal connectivity during the hours to days following learning. Further, we hypothesize that a "maintenance transcriptome" is subsequently induced that includes epigenetic negative regulators of gene expression, particularly histone deacetylases. The maintenance transcriptome negatively regulates the plasticity transcriptome, and thus the plastic capability of a neuron, after learning. In this way, the maintenance transcriptome would act as a metaplasticity mechanism that raises the threshold for change in neurons within an engram, helping to ensure the connectivity is stabilized and memory is maintained.
Early intervention in Alzheimer’s disease (AD) requires development of an easily administered tes... more Early intervention in Alzheimer’s disease (AD) requires development of an easily administered test able to identify those at risk. Focusing on microRNA robustly detected in plasma and standardizing the analysis, we sought to identify disease‐stage specific biomarkers.
Translation of synaptic mRNA contributes to alterations in the proteome necessary to consolidate ... more Translation of synaptic mRNA contributes to alterations in the proteome necessary to consolidate long-term potentiation (LTP), a model of memory processes. Yet, how this process is controlled is not fully resolved. MicroRNAs are non-coding RNAs that negatively regulate gene expression by suppressing translation or promoting mRNA degradation. As specific microRNAs are synaptically located, we hypothesized that they are ideally suited to couple synaptic activation, translational regulation, and LTP persistence. The aim of this study was to identify LTP-regulated microRNAs at or near synapses. Accordingly, LTP was induced unilaterally at perforant path-dentate gyrus synapses in awake adult Sprague-Dawley rats. Five hours later, dentate gyrus middle molecular layer neuropil, containing potentiated synapses, was laser-microdissected. MicroRNA expression profiling, using TaqMan Low Density MicroRNA Microarrays (n = 4), identified eight regulated microRNAs. Subsequent individual TaqMan ass...
The persistence and input specificity of long-term potentiation (LTP) make it attractive as a mec... more The persistence and input specificity of long-term potentiation (LTP) make it attractive as a mechanism of information storage. In its initial phase, both in vivo and in vitro studies have shown that LTP is associated with increased membrane localization of AMPA receptor subunits, but the molecular basis of LTP maintenance over the long-term is still unclear. We have previously shown that expression of AMPA and NMDA receptor subunits is elevated in whole homogenates prepared from dentate gyrus 48 h after LTP induction in vivo. In the present study, we utilized laser microdissection (LMD) techniques to determine whether AMPA and NMDA receptor upregulation occurs specifically in the stimulated regions of the dentate gyrus dendritic arbor. Receptor proteins GluN1, GluA1 and GluA2, as well as postsynaptic density protein of 95 kDa and tubulin were detected by Western blot analysis in microdissected samples. Gradients of expression were observed for GluN1 and GluA2, decreasing from the inner to the outer zones of the molecular layer, and were independent of LTP. When induced at medial perforant path synapses, LTP was associated with an apparent specific redistribution of GluA1 and GluN1 to the middle molecular layer that contains these synapses. These data indicate that glutamate receptor proteins are delivered specifically to dendritic regions possessing LTP-expressing synapses, and that these changes are preserved for at least 48 h.
Memory is fundamentally important to everyday life, and memory loss has devastating consequences ... more Memory is fundamentally important to everyday life, and memory loss has devastating consequences to individuals and society. Understanding the neurophysiological and cellular basis of memory paves the way for gaining insights into the molecular steps involved in memory formation, thereby revealing potential therapeutic targets for neurological diseases. For three decades, long-term potentiation (LTP) has been the gold standard synaptic model for mammalian memory mechanisms, in large part because of its long-lasting nature. Here, the authors summarize the characteristics of LTP persistence in the dentate gyrus of the hippocampus, comparing this with other hippocampal subregions and neocortex. They consider how long LTP can last and how its persistence is affected by subsequent behavioral experiences. Next, they review the molecular mechanisms known to contribute to LTP induction and persistence, in particular the role of new gene expression and protein synthesis and how they may be a...
Post-transcriptional control of gene expression by microRNAs provides an important regulatory sys... more Post-transcriptional control of gene expression by microRNAs provides an important regulatory system within neurons, allowing co-ordinate and fine-tuned expression of plasticity-related proteins. Indeed, specific microRNAs have been shown to be regulated by synaptic activity in the dentate gyrus, and contribute to the regulated gene expression that underlies the persistence of long-term potentiation (LTP), a model of memory. To fully explore the contribution of microRNAs in synaptic plasticity, it is important to characterize the complete microRNA transcriptome in regions such as the dentate gyrus. Accordingly we used deep sequencing and miRDeep* analysis to search for novel microRNAs expressed in the dentate gyrus granule cell layer. Drawing on combined sequencing and bioinformatics analyses, including hairpin stability and patterns of precursor microRNA processing, we identified nine putative novel microRNAs. We did not find evidence of differential expression of any of these putative microRNAs following LTP at perforant path-granule cell synapses in awake rats (5h post-tetanus; p>0.05). Focusing on novel_miR-1, the most abundant novel miRNA, we showed that this sequence could be amplified from RNA extracted from dentate gyrus granule cells by reverse transcription-quantitative polymerase chain reaction. Further, by computationally predicting mRNA targets of this microRNA, we found that this novel microRNA likely contributes to the regulation of proteins that function at synapses.
Pathological accumulation of tau protein in brain cells is the hallmark of a group of neurodegene... more Pathological accumulation of tau protein in brain cells is the hallmark of a group of neurodegenerative diseases called tauopathies. Accumulation of tau protein begins years before the onset of symptoms, which include deficits in cognition, behaviour and movement. The pre-symptomatic phase of tauopathy may be the best time to deliver disease-modifying treatments, but this is only possible if prognostic, pre-symptomatic biomarkers are identified. Here we describe the profiling of blood plasma microRNAs in a mouse model of tauopathy, in order to identify biomarkers of pre-symptomatic tauopathy. Circulating RNAs were isolated from blood plasma of 16-week-old and 53-week-old hTau mice and age-matched wild type controls (n = 28). Global microRNA profiling was performed using small RNA sequencing (Illumina) and selected microRNAs were validated using individual TaqMan RT-qPCR. The area under the receiver operating characteristic curve (AUC) was used to evaluate discriminative accuracy. We identified three microRNAs (miR-150-5p, miR-155-5p, miR-375-3p) that were down-regulated in 16-week-old hTau mice, which do not yet exhibit a behavioural phenotype and therefore represent pre-symptomatic tauopathy. The discriminative accuracy was AUC 0.98, 0.95 and 1, respectively. Downregulation of these microRNAs persisted at 53 weeks of age, when hTau mice exhibit cognitive deficits and advanced neuropathology. Bioinformatic analysis showed that these three microRNAs converge on pathways associated with neuronal signalling and phosphorylation of tau. Thus, these circulating microRNAs appear to reflect neuropathological change and are promising candidates in the development of biomarkers of pre-symptomatic tauopathy.
Astrocytes actively regulate numerous cell types both within and outside of the central nervous s... more Astrocytes actively regulate numerous cell types both within and outside of the central nervous system in health and disease. Indeed, astrocyte morphology, gene expression and function, alongside the content of astrocyte-derived extracellular vesicles (ADEVs), is significantly altered by ageing, inflammatory processes and in neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Here, we review the relevant emerging literature focussed on perturbation in expression of microRNA (miRNA), small non-coding RNAs that potently regulate gene expression. Synthesis of this literature shows that ageing-related processes, neurodegenerative disease-associated mutations or peptides and cytokines induce dysregulated expression of miRNA in astrocytes and in some cases can lead to selective incorporation of miRNA into ADEVs. Analysis of the miRNA targets shows that the resulting downstream consequences of alterations to levels of miRNA includ...
The 2012 International Joint Conference on Neural Networks (IJCNN), 2012
Long-term potentiation (LTP) is a long-lasting enhancement in signal transmission between two neu... more Long-term potentiation (LTP) is a long-lasting enhancement in signal transmission between two neurons, and represents a widely accepted experimental model for long-term memory processes. Although it is now clear that the maintenance of LTP requires new gene transcription, little is known on the genetic mechanisms underlying these changes. We assume that an LTP-related gene regulatory network has two equilibrium states in terms of gene expression levels which correspond to a pre-and post-LTP states. This network is shifted from the first to the latter by means of a perturbation, which experimentally corresponds to the high-frequency stimulus necessary to induce LTP in vivo. Based on this assumption and by means of modeling the transcriptional regulation with weight matrices, we study the properties of the main LTP-related network recently proposed in [1]. First, we classify the LTP-related genes according to their relevance to the bistable dynamic output of the network. In addition, we demonstrate how the LTP gene regulatory network architecture holds a higher tendency towards bistable behaviours than we should expect of a random network.
Current clinical tests for Parkinson’s disease (PD) provide insufficient diagnostic accuracy lead... more Current clinical tests for Parkinson’s disease (PD) provide insufficient diagnostic accuracy leading to an urgent need for improved diagnostic biomarkers. As microRNAs (miRNAs) are promising biomarkers of various diseases, including PD, this systematic review and meta-analysis aimed to assess the diagnostic accuracy of biofluid miRNAs in PD. All studies reporting data on miRNAs expression in PD patients compared to controls were included. Gene targets and significant pathways associated with miRNAs expressed in more than 3 biofluid studies with the same direction of change were analyzed using target prediction and enrichment analysis. A bivariate model was used to calculate sensitivity, specificity, likelihood ratios, and diagnostic odds ratio. While miR-24-3p and miR-214-3p were the most reported miRNA (7 each), miR-331-5p was found to be consistently up regulated in 4 different biofluids. Importantly, miR-19b-3p, miR-24-3p, miR-146a-5p, and miR-221-3p were reported in multiple stu...
RNA sequencing offers unprecedented access to the transcriptome. Key to this is the identificatio... more RNA sequencing offers unprecedented access to the transcriptome. Key to this is the identification and quantification of many different species of RNA from the same sample at the same time. In this study we describe a novel protocol for simultaneous detection of coding and non-coding transcripts using modifications to the Ion Total RNA-Seq kit v2 protocol, with integration of QIASeq FastSelect rRNA removal kit. We report highly consistent sequencing libraries can be produced from both frozen high integrity mouse hippocampal tissue and the more challenging post-mortem human tissue. Removal of rRNA using FastSelect was extremely efficient, resulting in less than 1.5% rRNA content in the final library. We identified > 30,000 unique transcripts from all samples, including protein-coding genes and many species of non-coding RNA, in biologically-relevant proportions. Furthermore, the normalized sequencing read count for select genes significantly negatively correlated with Ct values fr...
RNA sequencing offers unprecedented access to the transcriptome. Key to this is the identificatio... more RNA sequencing offers unprecedented access to the transcriptome. Key to this is the identification and quantification of many different species of RNA from the same sample at the same time. In this study we describe a novel protocol for simultaneous detection of coding and non-coding transcripts using modifications to the Ion Total RNA-Seq kit v2 protocol, with integration of QIASeq FastSelect rRNA removal kit. We report highly consistent sequencing libraries can be produced from both frozen high integrity mouse hippocampal tissue and the more challenging post-mortem human tissue. Removal of rRNA using FastSelect was highly efficient, resulting in less than 1.5% rRNA content in the final library, significantly better than other reported rRNA removal techniques. We identified >30,000 unique transcripts from all samples, including protein-coding genes and many unique species of non-coding RNA, in biologically-relevant proportions. Furthermore, normalized sequencing read count for s...
Secreted amyloid precursor protein-alpha (sAPPα) has growth factor-like properties and can modula... more Secreted amyloid precursor protein-alpha (sAPPα) has growth factor-like properties and can modulate long-term potentiation (LTP) and memory. Here, we demonstrate that exposure to sAPPα converts short-lasting LTP into protein-synthesis-dependent late LTP in hippocampal slices from male rats. sAPPβ had no discernable effect. We hypothesized that sAPPα facilitated LTP via regulated glutamate receptor trafficking andde novoprotein synthesis. We found using a linear mixed model that sAPPα stimulated trafficking of GluA2-lacking AMPARs, as well as NMDARs to the extrasynaptic cell surface, in a calcium/calmodulin-dependent kinase II and protein kinase G-dependent manner. Both cell surface receptor accumulation and LTP facilitation were present even after sAPPα washout and inhibition of receptor trafficking or protein synthesis prevented all these effects. Direct visualization of newly synthesized proteins (FUNCAT-PLA) confirmed the ability of sAPPα to stimulatede novoprotein synthesis and ...
The persistence and input specificity of long-term potentiation (LTP) make it attractive as a mec... more The persistence and input specificity of long-term potentiation (LTP) make it attractive as a mechanism of information storage. In its initial phase, both in vivo and in vitro studies have shown that LTP is associated with increased membrane localization of AMPA receptor subunits, but the molecular basis of LTP maintenance over the long-term is still unclear. We have previously shown that expression of AMPA and NMDA receptor subunits is elevated in whole homogenates prepared from dentate gyrus 48 h after LTP induction in vivo. In the present study, we utilized laser microdissection (LMD) techniques to determine whether AMPA and NMDA receptor upregulation occurs specifically in the stimulated regions of the dentate gyrus dendritic arbor. Receptor proteins GluN1, GluA1 and GluA2, as well as postsynaptic density protein of 95 kDa and tubulin were detected by Western blot analysis in microdissected samples. Gradients of expression were observed for GluN1 and GluA2, decreasing from the inner to the outer zones of the molecular layer, and were independent of LTP. When induced at medial perforant path synapses, LTP was associated with an apparent specific redistribution of GluA1 and GluN1 to the middle molecular layer that contains these synapses. These data indicate that glutamate receptor proteins are delivered specifically to dendritic regions possessing LTP-expressing synapses, and that these changes are preserved for at least 48 h.
How memories are maintained, and how memories are lost during aging or disease, are intensely inv... more How memories are maintained, and how memories are lost during aging or disease, are intensely investigated issues. Arguably, the reigning theory is that synaptic modifications allow for the formation of engrams during learning, and sustaining engrams sustains memory. Activity-regulated gene expression profiles have been shown to be critical to these processes, and their control by the epigenome has begun to be investigated in earnest. Here, we propose a novel theory as to how engrams are sustained. We propose that many of the genes that are currently believed to underlie long-term memory are actually part of a "plasticity transcriptome" that underpins structural and functional modifications to neuronal connectivity during the hours to days following learning. Further, we hypothesize that a "maintenance transcriptome" is subsequently induced that includes epigenetic negative regulators of gene expression, particularly histone deacetylases. The maintenance transcriptome negatively regulates the plasticity transcriptome, and thus the plastic capability of a neuron, after learning. In this way, the maintenance transcriptome would act as a metaplasticity mechanism that raises the threshold for change in neurons within an engram, helping to ensure the connectivity is stabilized and memory is maintained.
Early intervention in Alzheimer’s disease (AD) requires development of an easily administered tes... more Early intervention in Alzheimer’s disease (AD) requires development of an easily administered test able to identify those at risk. Focusing on microRNA robustly detected in plasma and standardizing the analysis, we sought to identify disease‐stage specific biomarkers.
Translation of synaptic mRNA contributes to alterations in the proteome necessary to consolidate ... more Translation of synaptic mRNA contributes to alterations in the proteome necessary to consolidate long-term potentiation (LTP), a model of memory processes. Yet, how this process is controlled is not fully resolved. MicroRNAs are non-coding RNAs that negatively regulate gene expression by suppressing translation or promoting mRNA degradation. As specific microRNAs are synaptically located, we hypothesized that they are ideally suited to couple synaptic activation, translational regulation, and LTP persistence. The aim of this study was to identify LTP-regulated microRNAs at or near synapses. Accordingly, LTP was induced unilaterally at perforant path-dentate gyrus synapses in awake adult Sprague-Dawley rats. Five hours later, dentate gyrus middle molecular layer neuropil, containing potentiated synapses, was laser-microdissected. MicroRNA expression profiling, using TaqMan Low Density MicroRNA Microarrays (n = 4), identified eight regulated microRNAs. Subsequent individual TaqMan ass...
The persistence and input specificity of long-term potentiation (LTP) make it attractive as a mec... more The persistence and input specificity of long-term potentiation (LTP) make it attractive as a mechanism of information storage. In its initial phase, both in vivo and in vitro studies have shown that LTP is associated with increased membrane localization of AMPA receptor subunits, but the molecular basis of LTP maintenance over the long-term is still unclear. We have previously shown that expression of AMPA and NMDA receptor subunits is elevated in whole homogenates prepared from dentate gyrus 48 h after LTP induction in vivo. In the present study, we utilized laser microdissection (LMD) techniques to determine whether AMPA and NMDA receptor upregulation occurs specifically in the stimulated regions of the dentate gyrus dendritic arbor. Receptor proteins GluN1, GluA1 and GluA2, as well as postsynaptic density protein of 95 kDa and tubulin were detected by Western blot analysis in microdissected samples. Gradients of expression were observed for GluN1 and GluA2, decreasing from the inner to the outer zones of the molecular layer, and were independent of LTP. When induced at medial perforant path synapses, LTP was associated with an apparent specific redistribution of GluA1 and GluN1 to the middle molecular layer that contains these synapses. These data indicate that glutamate receptor proteins are delivered specifically to dendritic regions possessing LTP-expressing synapses, and that these changes are preserved for at least 48 h.
Memory is fundamentally important to everyday life, and memory loss has devastating consequences ... more Memory is fundamentally important to everyday life, and memory loss has devastating consequences to individuals and society. Understanding the neurophysiological and cellular basis of memory paves the way for gaining insights into the molecular steps involved in memory formation, thereby revealing potential therapeutic targets for neurological diseases. For three decades, long-term potentiation (LTP) has been the gold standard synaptic model for mammalian memory mechanisms, in large part because of its long-lasting nature. Here, the authors summarize the characteristics of LTP persistence in the dentate gyrus of the hippocampus, comparing this with other hippocampal subregions and neocortex. They consider how long LTP can last and how its persistence is affected by subsequent behavioral experiences. Next, they review the molecular mechanisms known to contribute to LTP induction and persistence, in particular the role of new gene expression and protein synthesis and how they may be a...
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Papers by Joanna Williams