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Edwin J Weeber

Publications and source records attributed to Edwin J Weeber.

33 records · Page 2Linked to original sources
PubMed2003

Integrin requirement for hippocampal synaptic plasticity and spatial memory.

The establishment of memory requires coordinated signaling between presynaptic and postsynaptic terminals in the CNS. The integrins make up a large family of cell adhesion receptors that are known to mediate bidirectional signaling between cells or between cells and their external environment. We show here that many different integrins, including alpha3 and alpha5, are expressed broadly in the adult mouse brain and are associated with synapses. Mice with genetically reduced expression of alpha3 integrin fail to maintain long-term potentiation (LTP) generated in hippocampal CA1 neurons. Mice with reduced expression of the alpha3 and alpha5 integrins exhibit a defect in paired-pulse facilitation. Mice with reduced expression of alpha3, alpha5, and alpha8 are defective in hippocampal LTP and spatial memory in the water maze but have normal fear conditioning. These results demonstrate that several different integrins are involved in physiological plasticity and provide the first evidence of their requirement for behavioral plasticity in vertebrates.

Animals↗
PubMed2003

Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome.

Angelman syndrome (AS) is a disorder of human cognition characterized by severe mental retardation and epilepsy. Recently, a mouse model for AS (Ube3a maternal null mutation) was developed that displays deficits in both context-dependent learning and hippocampal long-term potentiation (LTP). In the present studies, we examined the molecular basis for these LTP and learning deficits. Mutant animals exhibited a significant increase in hippocampal phospho-calcium/calmodulin-dependent protein kinase II (CaMKII), specifically at sites Thr(286) and Thr(305), with no corresponding change in the levels of total CaMKII. In addition, mutants show a reduction in CaMKII activity, autophosphorylation capability, and total CaMKII associated with postsynaptic density. These findings are the first to implicate misregulation of CaMKII as a molecular cause for the neurobehavioral deficits in a human learning disorder.

Angelman Syndrome↗
PubMed2003

SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity.

We targeted 266 CAG repeats (a number that causes infantile-onset disease) into the mouse Sca7 locus to generate an authentic model of spinocerebellar ataxia type 7 (SCA7). These mice reproduced features of infantile SCA7 (ataxia, visual impairments, and premature death) and showed impaired short-term synaptic potentiation; downregulation of photoreceptor-specific genes, despite apparently normal CRX activity, led to shortening of photoreceptor outer segments. Wild-type ataxin-7 was barely detectable, as was mutant ataxin-7 in young animals; with increasing age, however, ataxin-7 staining became more pronounced. Neurons that appeared most vulnerable had relatively high levels of mutant ataxin-7; it is interesting, however, that marked dysfunction occurred in these neurons weeks prior to the appearance of nuclear inclusions. These data demonstrate that glutamine expansion stabilizes mutant ataxin-7, provide an explanation for selective neuronal vulnerability, and show that mutant ataxin-7 impairs posttetanic potentiation (PTP).

Animals↗
PubMed2003

Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior.

The central serotonin (5-HT) neurotransmitter system is an important modulator of diverse physiological processes and behaviors; however, the transcriptional mechanisms controlling its development are largely unknown. The Pet-1 ETS factor is a precise marker of developing and adult 5-HT neurons and is expressed shortly before 5-HT appears in the hindbrain. Here we show that in mice lacking Pet-1, the majority of 5-HT neurons fail to differentiate. Remaining ones show deficient expression of genes required for 5-HT synthesis, uptake, and storage. Significantly, defective development of the 5-HT system is followed by heightened anxiety-like and aggressive behavior in adults. These findings indicate that Pet-1 is a critical determinant of 5-HT neuron identity and implicate a Pet-1-dependent program in serotonergic modulation of behavior.

Aggression↗
PubMed2002

Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning.

Two apolipoprotein E (apoE) receptors, the very low density lipoprotein (VLDL) receptor and apoE receptor 2 (apoER2), are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. In the adult brain, Reelin is expressed by GABA-ergic interneurons, suggesting a potential function as a modulator of neurotransmission. ApoE receptors have been indirectly implicated in memory and neurodegenerative disorders because their ligand, apoE, is genetically associated with Alzheimer disease. We have used knockout mice to investigate the role of Reelin and its receptors in cognition and synaptic plasticity. Mice lacking either the VLDL receptor or the apoER2 show contextual fear conditioning deficits. VLDL receptor-deficient mice also have a moderate defect in long term potentiation (LTP), and apoER2 knockouts have a pronounced one. The perfusion of mouse hippocampal slices with Reelin has no effect on baseline synaptic transmission but significantly enhances LTP in area CA1. This Reelin-dependent augmentation of LTP is abolished in VLDL receptor and apoER2 knockout mice. Our results reveal a role for Reelin in controlling synaptic plasticity in the adult brain and suggest that both of its receptors are necessary for Reelin-dependent enhancement of synaptic transmission in the hippocampus. Thus, the impairment of apoE receptor-dependent neuromodulation may contribute to cognitive impairment and synaptic loss in Alzheimer disease.

Alzheimer Disease↗
PubMed2002

A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration.

To faithfully recreate the features of the human neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) in the mouse, we targeted 154 CAG repeats into the endogenous mouse locus. Sca1(154Q/2Q) mice developed a progressive neurological disorder that resembles human SCA1, featuring motor incoordination, cognitive deficits, wasting, and premature death, accompanied by Purkinje cell loss and age-related hippocampal synaptic dysfunction. Mutant ataxin-1 solubility varied with brain region, being most soluble in the neurons most vulnerable to degeneration. Solubility decreased overall as the mice aged; Purkinje cells, the most affected in SCA1, did not form aggregates of mutant protein until an advanced stage of disease. It appears that those neurons that cannot sequester the mutant protein efficiently and thereby curb its toxicity suffer the worst damage from polyglutamine-induced toxicity.

Animals↗
PubMed2002

Impaired conditioned fear and enhanced long-term potentiation in Fmr2 knock-out mice.

FRAXE mental retardation results from expansion and methylation of a CCG trinucleotide repeat located in exon 1 of the X-linked FMR2 gene, which results in transcriptional silencing. The product of FMR2 is a member of a family of proteins rich in serine and proline, members of which have been associated with transcriptional activation. We have developed a murine Fmr2 gene knock-out model by replacing a fragment containing parts of exon 1 and intron 1 with the Escherichia coli lacZ gene, placing lacZ under control of the Fmr2 promoter. Expression of lacZ in the knock-out animals indicates that Fmr2 is expressed in several tissues, including brain, bone, cartilage, hair follicles, lung, tongue, tendons, salivary glands, and major blood vessels. In the CNS, Fmr2 expression begins at the time that cells in the neuroepithelium differentiate into neuroblasts. Mice lacking Fmr2 showed a delay-dependent conditioned fear impairment. Long-term potentiation (LTP) was found to be enhanced in hippocampal slices of Fmr2 knock-out compared with wild-type littermates. To our knowledge, this mouse knock-out is the first example of an animal model of human mental retardation with impaired learning and memory performance and increased LTP. Thus, although a number of studies have suggested that diminished LTP is associated with memory impairment, our data suggest that increased LTP may be a mechanism that leads to impaired cognitive processing as well.

Animals↗
PubMed2002

The role of mitochondrial porins and the permeability transition pore in learning and synaptic plasticity.

Mitochondrial outer membrane permeability is conferred by a family of porin proteins. Mitochondrial porins conduct small molecules and constitute one component of the permeability transition pore that opens in response to apoptotic signals. Because mitochondrial porins have significant roles in diverse cellular processes including regulation of mitochondrial ATP and calcium flux, we sought to determine their importance in learning and synaptic plasticity in mice. We show that fear conditioning and spatial learning are disrupted in porin-deficient mice. Electrophysiological recordings of porin-deficient hippocampal slices reveal deficits in long and short term synaptic plasticity. Inhibition of the mitochondrial permeability transition pore by cyclosporin A in wild-type hippocampal slices reproduces the electrophysiological phenotype of porin-deficient mice. These results demonstrate a dynamic functional role for mitochondrial porins and the permeability transition pore in learning and synaptic plasticity.

Animals↗
PubMed2002

Molecular neurobiology of human cognition.

Recent studies into human mental retardation syndromes have given new insights into the molecular underpinnings of human cognitive processing, in particular into mechanisms likely to contribute to learning and memory. In this minireview, we present an overview of one signal transduction cascade that has garnered attention of late in this context, the ras/ERK/CREB pathway. We focus on this cascade because of recent exciting discoveries concerning the basis of neurofibromatosis type 1 (NF1) mental retardation, which link cognitive defects in this syndrome to disruptions of ras and its intracellular targets.

Animals↗
PubMed2002

Molecular genetics of human cognition.

Our understanding of the molecular underpinnings of human cognition has been greatly aided by the convergent synergy of clinical, genetic, and signaling research. By identifying the mutated genes that give rise to syndromes of mental retardation or cognitive defects in patients, and by placing the associated gene products within signaling networks, researchers are piecing together how learning occurs and how memories are formed and sustained.

Angelman Syndrome↗
PubMed2002

Protein kinase signal transduction cascades in mammalian associative conditioning.

One of the most intriguing and intensely studied questions facing contemporary neuroscientists involves the elucidation of the physiological mechanisms that underlie learning and memory. Recent advances have given us a much more detailed understanding of the signal transduction mechanisms subserving learning in the intact animal. One fact that has become clear is that activation of protein kinases and phosphorylation of their downstream effectors play a critical role. Four protein kinase cascades have garnered considerable attention in the study of information storage at both the synaptic and behavioral levels: Ca++/phospholipid-dependent protein kinase (PKC), Ca++/calmodulin-dependent protein kinase II (CaMKII), cAMP-dependent protein kinase (PKA), and extracellular signal-regulated kinase (ERK). This review will concentrate on studies of two behavioral tasks, conditioned fear and conditioned taste aversion, that provide evidence for the involvement of these kinase systems in associative learning. The authors will also examine a number of potential kinase substrates and how each could participate in the formation of long-term memories.

Animals↗
PubMed2002

Glutamate uptake in synaptic plasticity: from mollusc to mammal.

A great deal of research has been directed toward understanding the cellular mechanisms underlying synaptic plasticity and memory formation. To this point, most research has focused on the more "active" components of synaptic transmission: presynaptic transmitter release and postsynaptic transmitter receptors. Little work has been done characterizing the role neurotransmitter transporters might play during changes in synaptic efficacy. We review several new experiments that demonstrate glutamate transporters are regulated during changes in the efficacy of glutamatergic synapses. This regulation occurred during long-term facilitation of the sensorimotor synapse of Aplysia and long-term potentiation of the Schaffer-collateral synapse of the rat. We propose that glutamate transporters are "co-regulated" with other molecules/processes involved in synaptic plasticity, and that this process is phylogenetically conserved. These new findings indicate that glutamate transporters most likely play a more active role in neurotransmission than previously believed.

Amino Acid Transport System X-AG↗
PubMedDate not supplied

A role for ERK MAP kinase in physiologic temporal integration in hippocampal area CA1.

Recent studies demonstrate a requirement for the Extracellular signal Regulated Kinase (ERK) mitogen-activated protein kinase (MAPK) cascade in both the induction of long-lasting forms of hippocampal synaptic plasticity and in hippocampus-dependent associative and spatial learning. In the present studies, we investigated mechanisms by which ERK might contribute to synaptic plasticity at Schaffer collateral synapses in hippocampal slices. We found that long-term potentiation (LTP) induced with a pair of 100-Hz tetani does not require ERK activation in mice whereas it does in rats. However, in mice, inhibition of ERK activation blocked LTP induced by two LTP induction paradigms that mimicked the endogenous theta rhythm. In an additional series of studies, we found that mice specifically deficient in the ERK1 isoform of MAPK showed no impairments in tests of hippocampal physiology. To investigate ERK-dependent mechanisms operating during LTP-inducing stimulation paradigms, we monitored spike production in the cell body layer of the hippocampus during the period of theta-like LTP-inducing stimulation. Theta-burst stimulation (TBS) produced a significant amount of postsynaptic spiking, and the likelihood of spike production increased progressively over the course of the three trains of TBS independent of any apparent increase in Excitatory Post-Synaptic Potential (EPSP) magnitude. Inhibition of ERK activation dampened this TBS-associated increase in spiking. These data indicate that, for specific patterns of stimulation, ERK may function in the regulation of neuronal excitability in hippocampal area CA1. Overall, our data indicate that the progressive increase in spiking observed during TBS represents a form of physiologic temporal integration that is dependent on ERK MAPK activity.

Action Potentials↗