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J David Sweatt

Publications and source records attributed to J David Sweatt.

At least 19 recordsLinked to original sources
PubMed2019

Histone H3 lysine K4 methylation and its role in learning and memory.

Epigenetic modifications such as histone methylation permit change in chromatin structure without accompanying change in the underlying genomic sequence. A number of studies in animal models have shown that dysregulation of various components of the epigenetic machinery causes cognitive deficits at the behavioral level, suggesting that proper epigenetic control is necessary for the fundamental processes of learning and memory. Histone H3 lysine K4 (H3K4) methylation comprises one component of such epigenetic control, and global levels of this mark are increased in the hippocampus during memory formation. Modifiers of H3K4 methylation are needed for memory formation, shown through animal studies, and many of the same modifiers are mutated in human cognitive diseases. Indeed, all of the known H3K4 methyltransferases and four of the known six H3K4 demethylases have been associated with impaired cognition in a neurologic or psychiatric disorder. Cognitive impairment in such patients often manifests as intellectual disability, consistent with a role for H3K4 methylation in learning and memory. As a modification quintessentially, but not exclusively, associated with transcriptional activity, H3K4 methylation provides unique insights into the regulatory complexity of writing, reading, and erasing chromatin marks within an activated neuron. The following review will discuss H3K4 methylation and connect it to transcriptional events required for learning and memory within the developed nervous system. This will include an initial discussion of the most recent advances in the developing methodology to analyze H3K4 methylation, namely mass spectrometry and deep sequencing, as well as how these methods can be applied to more deeply understand the biology of this mark in the brain. We will then introduce the core enzymatic machinery mediating addition and removal of H3K4 methylation marks and the resulting epigenetic signatures of these marks throughout the neuronal genome. We next foray into the brain, discussing changes in H3K4 methylation marks within the hippocampus during memory formation and retrieval, as well as the behavioral correlates of H3K4 methyltransferase deficiency in this region. Finally, we discuss the human cognitive diseases connected to each H3K4 methylation modulator and summarize advances in developing drugs to target them.

Animals↗
PubMed2006

Deletion of Kv4.2 gene eliminates dendritic A-type K+ current and enhances induction of long-term potentiation in hippocampal CA1 pyramidal neurons.

Dendritic, backpropagating action potentials (bAPs) facilitate the induction of Hebbian long-term potentiation (LTP). Although bAPs in distal dendrites of hippocampal CA1 pyramidal neurons are attenuated when propagating from the soma, their amplitude can be increased greatly via downregulation of dendritic A-type K+ currents. The channels that underlie these currents thus may represent a key regulatory component of the signaling pathways that lead to synaptic plasticity. We directly tested this hypothesis by using Kv4.2 knock-out mice. Deletion of the Kv4.2 gene and a loss of Kv4.2 protein resulted in a specific and near-complete elimination of A-type K+ currents from the apical dendrites of CA1 pyramidal neurons. The absence of dendritic Kv4.2-encoded A-type K+ currents led to an increase of bAP amplitude and an increase of concurrent Ca2+ influx. Furthermore, CA1 pyramidal neurons lacking dendritic A-type K+ currents from Kv4.2 knock-out mice exhibited a lower threshold than those of wild-type littermates for LTP induction with the use of a theta burst pairing protocol. LTP triggered with the use of a saturating protocol, on the other hand, remained indistinguishable between Kv4.2 knock-out and wild-type neurons. Our results support the hypothesis that dendritic A-type K+ channels, composed of Kv4.2 subunits, regulate action potential backpropagation and the induction of specific forms of synaptic plasticity.

Action Potentials↗
PubMed2006

Secretin receptor-deficient mice exhibit impaired synaptic plasticity and social behavior.

Secretin is a peptide hormone released from the duodenum to stimulate the secretion of digestive juice by the pancreas. Secretin also functions as a neuropeptide hormone in the brain, and exogenous administration has been reported to alleviate symptoms in some patients with autism. We have generated secretin receptor-deficient mice to explore the relationship between secretin signaling in the brain and behavioral phenotypes. Secretin receptor-deficient mice are overtly normal and fertile; however, synaptic plasticity in the hippocampus is impaired and there are slightly fewer dendritic spines in the CA1 hippocampal pyramidal cells. Furthermore, secretin receptor-deficient mice show abnormal social and cognitive behaviors. These findings suggest that the secretin receptor system has an important role in the central nervous system relating to social behavior.

Animals↗
PubMed2006

Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation.

The ERK/MAP kinase cascade is important for long-term memory formation and synaptic plasticity, with a myriad of upstream signals converging upon ERK activation. Despite this convergence of signaling, neurons routinely activate appropriate biological responses to different stimuli. Scaffolding proteins represent a mechanism to achieve compartmentalization of signaling and the appropriate targeting of ERK-dependent processes. We report that kinase suppressor of Ras (KSR1) functions biochemically in the hippocampus to scaffold the components of the ERK cascade, specifically regulating the cascade when a membrane fraction of ERK is activated via a PKC-dependent pathway but not via a cAMP/PKA-dependent pathway. Specificity of KSR1-dependent signaling also extends to specific downstream targets of ERK. Behaviorally and physiologically, we found that the absence of KSR1 leads to deficits in associative learning and theta burst stimulation-induced LTP. Our report provides novel insight into the endogenous scaffolding role of KSR1 in controlling kinase activation within the nervous system.

Adrenergic beta-Agonists↗
PubMed2006

Regulation of nuclear factor kappaB in the hippocampus by group I metabotropic glutamate receptors.

An increasing amount of evidence suggests that the family of nuclear factor kappaB (NF-kappaB) transcription factors plays an important role in synaptic plasticity and long-term memory formation. The present study investigated the regulation of NF-kappaB family members p50, p65/RelA, and c-Rel in the hippocampus in response to metabotropic glutamate receptor (mGluR) signaling. Activation of group I metabotropic glutamate receptors (GpI-mGluRs) with the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) resulted in a time-dependent increase in DNA binding activity of p50, p65, and c-Rel in area CA1 of the hippocampus. An antagonist of mGluR5, 2-Methyl-6-(phenylethynyl)pyridine, inhibited the DHPG-induced activation of NF-kappaB, whereas an antagonist of mGluR1, (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid, did not. Using a series of inhibitors, we investigated the signaling pathways necessary for DHPG-induced activation of NF-kappaB and found that they included the phosphatidyl inositol 3-kinase, protein kinase C, mitogen-activated protein kinase kinase, and p38-mitogen-activated protein kinase pathways. To determine the functional significance of mGluR-induced regulation of NF-kappaB, we measured long-term depression (LTD) of Schaffer-collateral synapses in the hippocampus of c-Rel knock-out mice. Early phase LTD was normal in c-rel(-/-) mice. However, late-phase LTD (>90 min) was impaired in c-rel(-/-) mice. The observations of this deficit in hippocampal synaptic plasticity prompted us to further investigate long-term memory formation in c-rel(-/-) mice. c-rel(-/-) mice exhibited impaired performance in a long-term passive avoidance task, providing additional evidence for c-Rel in long-term memory formation. These results demonstrate that the NF-kappaB transcription factor family is regulated by GpI-mGluRs in the hippocampus and that the c-Rel transcription factor is necessary for long-term maintenance of LTD and formation of long-term memory.

Animals↗
PubMed2006

Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus.

DNA (cytosine-5) methylation represents one of the most widely used mechanisms of enduring cellular memory. Stable patterns of DNA methylation are established during development, resulting in creation of persisting cellular phenotypes. There is growing evidence that the nervous system has co-opted a number of cellular mechanisms used during development to subserve the formation of long term memory. In this study, we examined the role DNA (cytosine-5) methyltransferase (DNMT) activity might play in regulating the induction of synaptic plasticity. We found that the DNA within promoters for reelin and brain-derived neurotrophic factor, genes implicated in the induction of synaptic plasticity in the adult hippocampus, exhibited rapid and dramatic changes in cytosine methylation when DNMT activity was inhibited. Moreover, zebularine and 5-aza-2-deoxycytidine, inhibitors of DNMT activity, blocked the induction of long term potentiation at Schaffer collateral synapses. Activation of protein kinase C in the hippocampus decreased reelin promoter methylation and increased DNMT3A gene expression. Interestingly, DNMT activity is required for protein kinase C-induced increases in histone H3 acetylation. Considered together, these results suggest that DNMT activity is dynamically regulated in the adult nervous system and that DNMT may play a role in regulating the induction of synaptic plasticity in the mature CNS.

Animals↗
PubMed2006

Functional dissection of Reelin signaling by site-directed disruption of Disabled-1 adaptor binding to apolipoprotein E receptor 2: distinct roles in development and synaptic plasticity.

The Reelin signaling pathway controls neuronal positioning in human and mouse brain during development as well as modulation of long-term potentiation (LTP) and behavior in the adult. Reelin signals by binding to two transmembrane receptors, apolipoprotein E receptor 2 (Apoer2) and very-low-density lipoprotein receptor. After Reelin binds to the receptors, Disabled-1 (Dab1), an intracellular adaptor protein that binds to the cytoplasmic tails of the receptors, becomes phosphorylated on tyrosine residues, initiating a signaling cascade that includes activation of Src-family kinases and Akt. Here, we have created a line of mutant mice (Apoer2 EIG) in which the Apoer2 NFDNPVY motif has been altered to EIGNPVY to disrupt the Apoer2-Dab1 interaction to further study Reelin signaling in development and adult brain. Using primary neuronal cultures stimulated with recombinant Reelin, we find that normal Reelin signaling requires the wild-type NFDNPVY sequence and likely the interaction of Apoer2 with Dab1. Furthermore, examination of hippocampal, cortical, and cerebellar layering reveals that the NFDNPVY sequence of Apoer2 is indispensable for normal neuronal positioning during development of the brain. Adult Apoer2 EIG mice display severe abnormalities in LTP and behavior that are distinct from those observed for mice lacking Apoer2. In Apoer2 EIG slices, LTP degraded to baseline within 30 min, and this was prevented in the presence of Reelin. Together, these findings emphasize the complexity of Reelin signaling in the adult brain, which likely requires multiple adaptor protein interactions with the intracellular domain of Apoer2.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome.

Loss-of-function mutations or abnormal expression of the X-linked gene encoding methyl CpG binding protein 2 (MeCP2) cause a spectrum of postnatal neurodevelopmental disorders including Rett syndrome (RTT), nonsyndromic mental retardation, learning disability, and autism. Mice expressing a truncated allele of Mecp2 (Mecp2(308)) reproduce the motor and social behavior abnormalities of RTT; however, it is not known whether learning deficits are present in these animals. We investigated learning and memory, neuronal morphology, and synaptic function in Mecp2(308) mice. Hippocampus-dependent spatial memory, contextual fear memory, and social memory were significantly impaired in Mecp2(308) mutant males (Mecp2(308/Y)). The morphology of dendritic arborizations, the biochemical composition of synaptosomes and postsynaptic densities, and brain-derived neurotrophic factor expression were not altered in these mice. However, reduced postsynaptic density cross-sectional length was identified in asymmetric synapses of area CA1 of the hippocampus. In the hippocampus of symptomatic Mecp2(308/Y) mice, Schaffer-collateral synapses exhibited enhanced basal synaptic transmission and decreased paired-pulse facilitation, suggesting that neurotransmitter release was enhanced. Schaffer-collateral long-term potentiation (LTP) was impaired. LTP was also reduced in the motor and sensory regions of the neocortex. Finally, very early symptomatic Mecp2(308/Y) mice had increased basal synaptic transmission and deficits in the induction of long-term depression. These data demonstrate a requirement for MeCP2 in learning and memory and suggest that functional and ultrastructural synaptic dysfunction is an early event in the pathogenesis of RTT.

Animals↗
PubMed2006

Beta 1-integrins are required for hippocampal AMPA receptor-dependent synaptic transmission, synaptic plasticity, and working memory.

Integrins comprise a large family of cell adhesion receptors that mediate diverse biological events through cell-cell and cell-extracellular matrix interactions. Recent studies have shown that several integrins are localized to synapses with suggested roles in synaptic plasticity and memory formation. We generated a postnatal forebrain and excitatory neuron-specific knock-out of beta1-integrin in the mouse. Electrophysiological studies demonstrated that these mutants have impaired synaptic transmission through AMPA receptors and diminished NMDA receptor-dependent long-term potentiation. Despite the impairment in hippocampal synaptic transmission, the mutants displayed normal hippocampal-dependent spatial and contextual memory but were impaired in a hippocampal-dependent, nonmatching-to-place working memory task. These phenotypes parallel those observed in animals carrying knock-outs of the GluR1 (glutamate receptor subunit 1) subunit of the AMPA receptor. These observations suggest a new function of beta1-integrins as regulators of synaptic glutamate receptor function and working memory.

Animals↗
PubMed2006

Signal transduction mechanisms in memory disorders.

This chapter explores some of the molecular events contributing to memory formation and how, when these events malfunction, disturbances in memory occur. After a brief discussion of signaling in the hippocampus, we will explore the topics of human mental retardation syndromes that involve disruption of these processes, including Angelman syndrome (AS), Neurofibromatosis 1 (NF1)-associated learning disorders, Coffin-Lowry syndrome (CLS), Rubinstein-Taybi syndrome (RTS), and Rett syndrome (RTT).

Animals↗
PubMed2005

ERK/MAPK regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit.

Kv4.2 is the primary pore-forming subunit encoding A-type currents in many neurons throughout the nervous system, and it also contributes to the transient outward currents of cardiac myocytes. A-type currents in the dendrites of hippocampal CA1 pyramidal neurons are regulated by activation of ERK/MAPK, and Kv4.2 is the likely pore-forming subunit of that current. We showed previously that Kv4.2 is directly phosphorylated at three sites by ERK/MAPK (T602, T607, and S616). In this study we determined whether direct phosphorylation of Kv4.2 by ERK/MAPK is responsible for the regulation of the A-type current observed in neurons. We made site-directed mutants, changing the phosphosite serine (S) or threonine (T) to aspartate (D) to mimic phosphorylation. We found that the T607D mutation mimicked the electrophysiological changes elicited by ERK/MAPK activation in neurons: a rightward shift of the activation curve and an overall reduction in current compared with wild type (WT). Surprisingly, the S616D mutation caused the opposite effect, a leftward shift in the activation voltage. K(+) channel-interacting protein (KChIP)3 ancillary subunit coexpression with Kv4.2 was necessary for the T607D effect, as the T607D mutant when expressed in the absence of KChIP3 was not different from WT Kv4.2. These data suggest that direct phosphorylation of Kv4.2 at T607 is involved in the dynamic regulation of the channel function by ERK/MAPK and an interaction of the primary subunit with KChIP is also necessary for this effect. Overall these studies provide new insights into the structure-function relationships for MAPK regulation of membrane ion channels.

Amino Acid Substitution↗
PubMed2005

Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2.

Apolipoprotein E receptor 2 (Apoer2), a member of the LDL receptor gene family, and its ligand Reelin control neuronal migration during brain development. Apoer2 is also essential for induction of long-term potentiation (LTP) in the adult brain. Here we show that Apoer2 is present in the postsynaptic densities of excitatory synapses where it forms a functional complex with NMDA receptors. Reelin signaling through Apoer2 markedly enhances LTP through a mechanism that requires the presence of amino acids encoded by an exon in the intracellular domain of Apoer2. This exon is alternatively spliced in an activity-dependent manner and is required for Reelin-induced tyrosine phosphorylation of NMDA receptor subunits. Mice constitutively lacking the exon perform poorly in learning and memory tasks. Thus, alternative splicing of Apoer2, a novel component of the NMDA receptor complex, controls the modulation of NMDA receptor activity, synaptic neurotransmission, and memory by Reelin.

Alternative Splicing↗
PubMed2005

Epigenetic mechanisms in memory formation.

Discoveries concerning the molecular mechanisms of cell differentiation and development have dictated the definition of a new sub-discipline of genetics known as epigenetics. Epigenetics refers to a set of self-perpetuating, post-translational modifications of DNA and nuclear proteins that produce lasting alterations in chromatin structure as a direct consequence, and lasting alterations in patterns of gene expression as an indirect consequence. The area of epigenetics is a burgeoning subfield of genetics in which there is considerable enthusiasm driving new discoveries. Neurobiologists have only recently begun to investigate the possible roles of epigenetic mechanisms in behaviour, physiology and neuropathology. Strikingly, the relevant data from the few extant neurobiology-related studies have already indicated a theme - epigenetic mechanisms probably have an important role in synaptic plasticity and memory formation.

Animals↗
PubMed2004

Mild overexpression of MeCP2 causes a progressive neurological disorder in mice.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wild-type human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2(Tg1), which expresses MeCP2 at approximately 2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, became hypoactive and approximately 30% of them died by 1 year of age. These data demonstrate that MeCP2 levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.

Animals↗
PubMed2004

Regulation of histone acetylation during memory formation in the hippocampus.

Formation of long term memory begins with the activation of many disparate signaling pathways that ultimately impinge on the cellular mechanisms regulating gene expression. We investigated whether mechanisms regulating chromatin structure were activated during the early stages of long term memory formation in the hippocampus. Specifically, we investigated hippocampal histone acetylation during the initial stages of consolidation of long term association memories in a contextual fear conditioning paradigm. Acetylation of histone H3 in area CA1 of the hippocampus was regulated in contextual fear conditioning, an effect dependent on activation of N-methyl-D-aspartic acid (NMDA) receptors and ERK, and blocked using a behavioral latent inhibition paradigm. Activation of NMDA receptors in area CA1 in vitro increased acetylation of histone H3, and this effect was blocked by inhibition of ERK signaling. Moreover, activation of ERK in area CA1 in vitro through either the protein kinase C or protein kinase A pathways, biochemical events known to be involved in long term memory formation, also increased histone H3 acetylation. Furthermore, we observed that elevating levels of histone acetylation through the use of the histone deacetylase inhibitors trichostatin A or sodium butyrate enhanced induction of long term potentiation at Schaffer-collateral synapses in area CA1 of the hippocampus, a candidate mechanism contributing to long term memory formation in vivo. In concert with our findings in vitro, injection of animals with sodium butyrate prior to contextual fear conditioning enhanced formation of long term memory. These results indicate that histone-associated heterochromatin undergoes changes in structure during the formation of long term memory. Mimicking memory-associated changes in heterochromatin enhances a cellular process thought to underlie long term memory formation, hippocampal long term potentiation, and memory formation itself.

Acetylation↗
PubMed2004

A bioinformatics analysis of memory consolidation reveals involvement of the transcription factor c-rel.

Consolidation of long-term memory (LTM) is a complex process requiring synthesis of new mRNAs and proteins. Many studies have characterized the requirement for de novo mRNA and protein synthesis; however, few studies have comprehensively identified genes regulated during LTM consolidation. We show that consolidation of long-term contextual memory in the hippocampus triggers altered expression of numerous genes encompassing many aspects of neuronal function. Like contextual memory formation, this altered gene expression required NMDA receptor activation and was specific for situations in which the animal formed an association between a physical context and a sensory stimulus. Using a bioinformatics approach, we found that regulatory elements for several transcription factors are over-represented in the upstream region of genes regulated during consolidation of LTM. Using a knock-out mouse, we found that c-rel, one of the transcription factors identified in our bioinformatics study, is necessary for hippocampus-dependent long-term memory formation.

Animals↗