[Show abstract][Hide abstract] ABSTRACT: We summarize the reviews and research papers submitted by speakers at a discussion meeting on Synaptic Plasticity in Health and Disease held at the Royal Society, London on 2-3 December 2013, and a subsequent satellite meeting convened at the Royal Society/Kavli Centre at Chicheley Hall on 4-5 December 2013. Together, these contributions give an overview of current research and controversies in a vibrant branch of neuroscience with important implications for the understanding of many forms of learning and memory, and a wide spectrum of neurological and cognitive disorders.
Philosophical Transactions of The Royal Society B Biological Sciences 01/2014; 369(1633):20130129. DOI:10.1098/rstb.2013.0129 · 7.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Long-term potentiation and long-term depression are enduring changes in synaptic strength, induced by specific patterns of synaptic activity, that have received much attention as cellular models of information storage in the central nervous system. Work in a number of brain regions, from the spinal cord to the cerebral cortex, and in many animal species, ranging from invertebrates to humans, has demonstrated a reliable capacity for chemical synapses to undergo lasting changes in efficacy in response to a variety of induction protocols. In addition to their physiological relevance, long-term potentiation and depression may have important clinical applications. A growing insight into the molecular mechanisms underlying these processes, and technological advances in non-invasive manipulation of brain activity, now puts us at the threshold of harnessing long-term potentiation and depression and other forms of synaptic, cellular and circuit plasticity to manipulate synaptic strength in the human nervous system. Drugs may be used to erase or treat pathological synaptic states and non-invasive stimulation devices may be used to artificially induce synaptic plasticity to ameliorate conditions arising from disrupted synaptic drive. These approaches hold promise for the treatment of a variety of neurological conditions, including neuropathic pain, epilepsy, depression, amblyopia, tinnitus and stroke.
[Show abstract][Hide abstract] ABSTRACT: The NMDA receptor (NMDAR) subunit GluN1 is an obligatory component of NMDARs without a known functional homolog and is expressed in almost every neuronal cell type. The NMDAR system is a coincidence detector with critical roles in spatial learning and synaptic plasticity. Its coincidence detection property is crucial for the induction of hippocampal long-term potentiation (LTP). We have generated a mutant mouse model expressing a hypomorph of the Grin1(N598R) allele, which leads to a minority (about 10%) of coincidence detection-impaired NMDARs. Surprisingly, these animals revealed specific functional changes in the dentate gyrus (DG) of the hippocampal formation. Early LTP was expressed normally in area CA1 in vivo, but was completely suppressed at perforant path-granule cell synapses in the DG. In addition, there was a pronounced reduction in the amplitude of the evoked population spike in the DG. These specific changes were accompanied by behavioral impairments in spatial recognition, spatial learning, reversal learning, and retention. Our data show that minor changes in GluN1-dependent NMDAR physiology can cause dramatic consequences in synaptic signaling in a subregion-specific fashion despite the nonredundant nature of the GluN1 gene and its global expression.
[Show abstract][Hide abstract] ABSTRACT: Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of human chromosome 21 (Hsa21). Recently, O'Doherty et al. [An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science 309 (2005) 2033-2037] generated a trans-species aneuploid mouse line (Tc1) that carries an almost complete Hsa21. The Tc1 mouse is the most complete animal model for DS currently available. Tc1 mice show many features that relate to human DS, including alterations in memory, synaptic plasticity, cerebellar neuronal number, heart development and mandible size. Because motor deficits are one of the most frequently occurring features of DS, we have undertaken a detailed analysis of motor behaviour in cerebellum-dependent learning tasks that require high motor coordination and balance. In addition, basic electrophysiological properties of cerebellar circuitry and synaptic plasticity have been investigated. Our results reveal that, compared with controls, Tc1 mice exhibit a higher spontaneous locomotor activity, a reduced ability to habituate to their environments, a different gait and major deficits on several measures of motor coordination and balance in the rota rod and static rod tests. Moreover, cerebellar long-term depression is essentially normal in Tc1 mice, with only a slight difference in time course. Our observations provide further evidence that support the validity of the Tc1 mouse as a model for DS, which will help us to provide insights into the causal factors responsible for motor deficits observed in persons with DS.
Human Molecular Genetics 02/2009; 18(8):1449-63. DOI:10.1093/hmg/ddp055 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Synaptic efficacy following long-term potentiation (LTP) and memory consolidation is associated with changes in the expression of immediate early genes (IEGs). These changes are often accompanied by increased expression of glial fibrillary acidic protein (GFAP). While the protein products of the majority of IEGs are mainly restricted to the cell body, Arg3.1/Arc product is rapidly delivered to dendrites, where it accumulates close to synaptic sites. Arg3.1/Arc protein was originally considered neurone specific; however, we have recently found Arg3.1/Arc immunoreactivity (Arg3.1/Arc-IR) within glial cells and demonstrated its increased expression after LTP in the hippocampal dentate gyrus (DG). Here, we have further investigated this novel finding, using electron microscopic immunocytochemistry to determine the localization and sub-cellular distribution of Arg3.1/Arc protein in GFAP positive glia (GFAP-IR) in the DG. Arg3.1/Arc labelling was seen prominently in GFAP-IR glial cell bodies and in large- and medium-sized glial filamentous processes. GFAP-labelled medium-small peri-synaptic glial profiles also displayed Arg3.1/Arc-IR; however, the very thin and distal glial filaments only displayed Arc-IR. Arc-IR was distributed throughout the cytoplasm, often associated with GFAP filaments, and along the plasma membrane of glial processes. Peri-synaptic glial Arg3.1/Arc-IR processes were apposed to pre- and/or post-synaptic profiles at asymmetric axospinous synapses. These data, taken with our earlier study which provided evidence for an increase in astrocytic Arg3.1/Arc-IR after the induction of LTP, suggest a role for glial Arg3.1/Arc in structural and synaptic plasticity which may be critical for the maintenance of cognitive functions.
Journal of Cellular and Molecular Medicine 04/2008; 12(2):671-8. DOI:10.1111/j.1582-4934.2007.00105.x · 4.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O'Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a detailed analysis of cognitive function and synaptic plasticity in Tc1 mice. Here we show that Tc1 mice have impaired spatial working memory (WM) but spared long-term spatial reference memory (RM) in the Morris watermaze. Similarly, Tc1 mice are selectively impaired in short-term memory (STM) but have intact long-term memory (LTM) in the novel object recognition task. The pattern of impaired STM and normal LTM is paralleled by a corresponding phenotype in long-term potentiation (LTP). Freely-moving Tc1 mice exhibit reduced LTP 1 h after induction but normal maintenance over days in the dentate gyrus of the hippocampal formation. Biochemical analysis revealed a reduction in membrane surface expression of the AMPAR (alpha-amino-3-hydroxy-5-methyl-4-propionic acid receptor) subunit GluR1 in the hippocampus of Tc1 mice, suggesting a potential mechanism for the impairment in early LTP. Our observations also provide further evidence that STM and LTM for hippocampus-dependent tasks are subserved by parallel processing streams.
[Show abstract][Hide abstract] ABSTRACT: Autophosphorylation of alpha-Ca2+/calmodulin kinase II (alphaCaMKII) at Thr286 is thought to be a general effector mechanism for sustaining transcription-independent long-term potentiation (LTP) at pathways where LTP is NMDA receptor-dependent. We have compared LTP at two such hippocampal pathways in mutant mice with a disabling point mutation at the Thr286 autophosphorylation site. We find that autophosphorylation of alphaCaMKII is essential for induction of LTP at Schaffer commissural-CA1 synapses in vivo, but is not required for LTP that can be sustained over days at medial perforant path-granule cell synapses in awake mice. At these latter synapses LTP is supported by cyclic AMP-dependent signalling in the absence of alphaCaMKII signalling. Thus, the autophosphorylation of alphaCaMKII is not a general requirement for NMDA receptor-dependent LTP in the adult mouse.
The Journal of Physiology 09/2006; 574(Pt 3):805-18. DOI:10.1113/jphysiol.2006.111559 · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Long-term potentiation (LTP) is a well-characterized form of synaptic plasticity that fulfils many of the criteria for a neural correlate of memory. LTP has been studied in a variety of animal models and, in rodents in particular, there is now a strong body of evidence demonstrating common underlying molecular mechanisms in LTP and memory. Results are beginning to emerge from studies of neural plasticity in humans. This review will summarize findings demonstrating that synaptic LTP can be induced in human CNS tissue and that rodent and human LTP probably share similar molecular mechanisms. We will also discuss the application of non-invasive stimulation techniques to awake human subjects to induce LTP-like long-lasting changes in localized neural activity. These techniques have potential therapeutic application in manipulating neural plasticity to treat a variety of conditions, including depression, Parkinson's disease, epilepsy and neuropathic pain.
[Show abstract][Hide abstract] ABSTRACT: Aneuploidies are common chromosomal defects that result in growth and developmental deficits and high levels of lethality in humans. To gain insight into the biology of aneuploidies, we manipulated mouse embryonic stem cells and generated a trans-species aneuploid mouse line that stably transmits a freely segregating, almost complete human chromosome 21 (Hsa21). This "transchromosomic" mouse line, Tc1, is a model of trisomy 21, which manifests as Down syndrome (DS) in humans, and has phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, heart development, and mandible size that relate to human DS. Transchromosomic mouse lines such as Tc1 may represent useful genetic tools for dissecting other human aneuploidies.
[Show abstract][Hide abstract] ABSTRACT: p25, a degradation product of p35, has been reported to accumulate in the forebrain of patients with Alzheimer's disease. p25 as well as p35 are activators of cyclin-dependent kinase 5 (Cdk5) although p25/Cdk5 and p35/Cdk5 complexes have distinct properties. Several mouse models with high levels of p25 expression exhibit signs of neurodegeneration. On the contrary, we have shown that low levels of p25 expression do not cause neurodegeneration and are even beneficial for particular types of learning and memory [Angelo et al., (2003) Eur J. Neurosci., 18, 423-431]. Here, we have studied the influence of low-level p25 expression in hippocampal synaptic plasticity and in learning and memory for each sex separately in two different genetic backgrounds (129B6F1 and C57BL/6). Surprisingly, we found that low-level p25 expression had different consequences in male and female mutants. In the two genetic backgrounds LTP induced by a strong stimulation of the Schaffer's collaterals (four trains, 1-s duration, 5-min interval) was severely impaired in male, but not in female, p25 mutants. Furthermore, in the two genetic backgrounds spatial learning in the Morris water maze was faster in female p25 mutants than in male transgenic mice. These results suggest that, in women, the production of p25 in Alzheimer's disease could be a compensation for some early learning and memory deficits.
European Journal of Neuroscience 07/2005; 21(11):3023-33. DOI:10.1111/j.1460-9568.2005.04137.x · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Electron microscopic immunocytochemical methods were used to determine the localization, subcellular distribution and expression of activity-regulated cytoskeletal protein (Arc/Arg3.1) in dentate gyrus after unilateral induction of long-term potentiation (LTP) in the perforant pathway of anaesthetized rats. At 2 h post-induction, immunoreaction product was visible in the dentate gyrus in both the granule cell and molecular layers. Arc expression was higher in the potentiated than the unstimulated contralateral hemisphere. Single-section electron microscopy analysis in unstimulated tissue and in tissue prepared 2 and 4 h after LTP induction showed Arc immunoreactivity (Arc-IR) in dendrites, dendritic spines and glia. Arc-IR was associated with synaptic and non-synaptic plasma membrane apposed to axon terminals and with cytoplasmic organelles, including the cytoskeleton. Arc-IR was also present in neuronal perikarya and there was occasional labelling of nuclei and axons. At 2 h post-LTP induction, there were significant increases in Arc-IR within the granule cell and molecular layers of the dentate gyrus and particularly within the middle molecular layer relative to the inner and outer molecular layers. This increase in Arc expression 2 h after LTP induction was blocked by the N-methyl-D-aspartate receptor antagonist (RS)-3-2-carboxypiperazin-4-yl-propyl-1-phosphonic acid. In animals killed 4 h after LTP induction, Arc expression had declined and differences between the potentiated and unpotentiated hemispheres were no longer significant. Our data provide ultrastructural evidence for a transient LTP-associated increase in the expression of Arc protein in the middle molecular layer of the dentate gyrus, with preferential targeting to dendrites, dendritic spines and glia.
European Journal of Neuroscience 06/2005; 21(9):2384-96. DOI:10.1111/j.1460-9568.2005.04068.x · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A major role has been postulated for a maintained increase in the autonomous activity of CaMKII in the expression of long-term potentiation (LTP). However, attempts to inhibit the expression of LTP with CaMKII inhibitors have yielded inconsistent results. Here we compare the changes in CaMKII autonomous activity and phosphorylation at Thr286 of alphaCaMKII in rat hippocampal slices using chemical or tetanic stimulation to produce either LTP or short-term potentiation (STP). Tetanus-induced LTP in area CA1 requires CaMKII activation and Thr286 phosphorylation of alphaCaMKII, but we did not observe an increase in autonomous activity. Next we induced LTP by 10 min exposure to 25 mM tetraethyl-ammonium (TEA) or 5 min exposure to 41 mM potassium (K) after pretreatment with calyculin A. Exposure to K alone produced STP. These protocols allowed us to monitor temporal changes in autonomous activity during and after exposure to the potentiating chemical stimulus. In chemically induced LTP, autonomous activity was maximally increased within 30 s whereas this increase was significantly delayed in STP. However, in both LTP and STP the two-fold increase in autonomous activity measured immediately after stimulation was short-lived, returning to baseline within 2-5 min after re-exposure to normal ACSF. In LTP, but not in STP, the phosphorylation of alphaCaMKII at Thr286 persisted for at least 60 min after stimulation. These results confirm that LTP is associated with a maintained increase in autophosphorylation at Thr286 but indicate that a persistent increase in the autonomous activity of CaMKII is not required for the expression of LTP.
European Journal of Neuroscience 01/2005; 20(11):3063-72. DOI:10.1111/j.1460-9568.2004.03748.x · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have isolated a novel transcript with homology to the major microtubule-associated protein in dividing sea urchin embryos, EMAP. The protein has a predicted MW of approximately 180 kDa and we have named it Eml5 (EMAP-like protein 5). Eml5 contains 11 putative WD40 domains and 3 hydrophobic stretches of 43 aa, HELP domains, which have been suggested to be involved in microtubule binding. Eml5 appears to consist of two tandem repeats of the complete EMAP protein separated by a putative dimerization domain. Eml5 mRNA and protein is expressed at high levels in the hippocampus, cerebellum and olfactory bulb, as determined by in situ hybridization and immunocytochemistry. Eml5 transcripts can be detected in fore- and hindbrain structures from embryonic day 13 onwards. Because other EMAP-like proteins are involved in regulating microtubule dynamics, it is likely that Eml5 plays a role in the regulation of cytoskeletal rearrangements during neuronal development and in adult brain
[Show abstract][Hide abstract] ABSTRACT: We employed differential display of expressed mRNAs (Liang, P., and Pardee, A. B. (1992) Science 257, 967-971) to identify genes up-regulated after long term potentiation (LTP) induction in the hippocampus of awake adult rats. In situ hybridization confirmed the differential expression of five independently amplified clones representing two distinct transcripts, cl13/19/90 and cl95/96. Neither cl13/19/90 nor cl95/96 showed significant sequence homology to known transcripts (mRNA or expressed sequence tag) or to the mouse or human genome. However, comparison with the rat genome revealed that they are localized to a predicted intron of the phosphodiesterase Pde10A gene. cl13/19/90 and cl95/96 are likely to be part of the Pde10A primary transcript as, using reverse transcriptase-PCR, we could specifically amplify distinct introns of the Pde10A primary transcript, and in situ hybridization demonstrated that a subset of Pde10A splice variants are also up-regulated after LTP induction. These results indicate that amplification of a primary transcript can faithfully report gene activity and that differential display can be used to identify differential expression of RNA species other than mRNA. In transiently transfected Cos7 cells, Pde10A3 reduces the atrial natriuretic peptide-induced elevation in cGMP levels without affecting basal cGMP levels. This cellular function of LTP-associated Pde10A transcripts argues for a role of the cGMP/cGMP-dependent kinase pathway in long term synaptic plasticity.
[Show abstract][Hide abstract] ABSTRACT: In anaesthetised rats, long-term potentiation (LTP) was induced unilaterally in the dentate gyrus by tetanic stimulation of the perforant path. Animals were killed 6 h after LTP induction and dendritic spines and synapses in tetanised and untetanised (contralateral) hippocampal tissue from the middle molecular layer (MML) were examined in the electron microscope using stereological analysis. Three-dimensional reconstructions were also used for the first time in LTP studies in vivo, with up to 130 ultrathin serial sections analysed per MML dendritic segment. A volume sampling procedure revealed no significant changes in hippocampal volume after LTP and an unbiased counting method demonstrated no significant changes in synapse density in potentiated compared with control tissue. In the potentiated hemisphere, there were changes in the proportion of different spine types and their synaptic contacts. We found an increase in the percentage of synapses on thin dendritic spines, a decrease in synapses on both stubby spines and dendritic shafts, but no change in the proportion of synapses on mushroom spines. Analysis of three-dimensional reconstructions of thin and mushroom spines following LTP induction revealed a significant increase in their volume and area. We also found an increase in volume and area of unperforated (macular) and perforated (segmented) postsynaptic densities. Our data demonstrate that whilst there is no change in synapse density 6 h after the induction of LTP in vivo, there is a considerable restructuring of pre-existing synapses, with shaft and stubby spines transforming to thin dendritic spines, and mushroom spines changing only in shape and volume.
[Show abstract][Hide abstract] ABSTRACT: The late temporal component of long-term potentiation (LTP), a putative neural mechanism for information storage in the brain, is protein synthesis-dependent, but the site of obligatory protein synthesis is not known. Here we show that when the protein synthesis inhibitor emetine is applied locally to the apical dendritic field of CA1 pyramidal cells in the murine hippocampus, late LTP is impaired at apical but not at basal dendrites, and conversely when emetine is applied locally to basal dendrites, late LTP is impaired only at basal dendrites. Thus, local protein synthesis modulates the expression of tetanically induced late LTP at Schaffer-commissural synapses on CA1 pyramidal cells.
European Journal of Neuroscience 01/2004; 18(11):3150-2. DOI:10.1111/j.1460-9568.2003.03054.x · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mechanisms by which long-term potentiation (LTP) is expressed are controversial, with evidence for both presynaptic and postsynaptic involvement. We have used confocal microscopy and Ca(2+)-sensitive dyes to study LTP at individual visualized synapses. Synaptically evoked Ca(2+) transients were imaged in distal dendritic spines of pyramidal cells in cultured hippocampal slices, before and after the induction of LTP. At most synapses, from as early as 10 min to at least 60 min after induction, LTP was associated with an increase in the probability of a single stimulus evoking a postsynaptic Ca(2+) response. These observations provide compelling evidence of a presynaptic component to the expression of early LTP at Schaffer-associational synapses. In most cases, the store-dependent evoked Ca(2+) transient in the spine was also increased after induction, a novel postsynaptic aspect of LTP.
[Show abstract][Hide abstract] ABSTRACT: We have examined the effect of arachidonic acid on the transient increases in intracellular Ca2+ evoked by NMDA and AMPA in cultured hippocampal pyramidal cells loaded with Fura-2 AM. Repeated brief pulses of NMDA elicited Ca2+ transients that showed a modest run down. This run down was enhanced if the preparation was shielded from UV light and was reduced by conducting the experiments in the presence of the nitric oxide synthase inhibitor l-nitroarginine (100 micro m). Arachidonic acid (2 micro m) enhanced the Ca2+ transients evoked by NMDA but not those evoked by AMPA. Other C20 unsaturated fatty acids did not alter the time course of the response to NMDA. These experiments suggest that elevated intracellular Ca2+ activates nitric oxide synthase and the resulting synthesis of nitric oxide depresses the Ca2+ response to NMDA while arachidonic acid augments these responses. Therefore two substances implicated in synaptic plasticity (arachidonic acid and nitric oxide) differentially modulate NMDA-mediated Ca2+ entry into hippocampal neurons.
European Journal of Neuroscience 07/2003; 17(11):2323-8. DOI:10.1046/j.1460-9568.2003.02671.x · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the mid-1960s, it was generally agreed that the engram, the neural trace of previously experienced events, must be encoded by Hebb-like neurons in which synaptic efficacy could be modified by activity. Here, I describe my attempts as a PhD student at McGill University, Montreal, to find rules governing cortical plasticity in the neocortex, and having failed, why the hippocampus seemed to offer a far better prospect.
Philosophical Transactions of The Royal Society B Biological Sciences 05/2003; 358(1432):621-3. DOI:10.1098/rstb.2002.1227 · 7.06 Impact Factor