Hippocampal LTP Research Articles

α-Calcium calmodulin kinase II modulates the temporal structure of hippocampal bursting patterns.

The alpha calcium calmodulin kinase II (α-CaMKII) is known to play a key role in CA1/CA3 synaptic plasticity, hippocampal place cell stability and spatial learning. Additionally, there is evidence from hippocampal electrophysiological slice studies that this kinase has a role in regulating ion channels that control neuronal excitability. Here, we report in vivo single unit studies, with α-CaMKII mutant mice, in which threonine 305 was replaced with an aspartate (α-CaMKIIT305D mutants), that indicate that this kinase modulates spike patterns in hippocampal pyramidal neurons. Previous studies showed that α-CaMKIIT305D mutants have abnormalities in both hippocampal LTP and hippocampal-dependent learning. We found that besides decreased place cell stability, which could be caused by their LTP impairments, the hippocampal CA1 spike patterns of α-CaMKIIT305D mutants were profoundly abnormal. Although overall firing rate, and overall burst frequency were not significantly altered in these mutants, inter-burst intervals, mean number of intra-burst spikes, ratio of intra-burst spikes to total spikes, and mean intra-burst intervals were significantly altered. In particular, the intra burst intervals of place cells in α-CaMKIIT305D mutants showed higher variability than controls. These results provide in vivo evidence that besides its well-known function in synaptic plasticity, α-CaMKII, and in particular its inhibitory phosphorylation at threonine 305, also have a role in shaping the temporal structure of hippocampal burst patterns. These results suggest that some of the molecular processes involved in acquiring information may also shape the patterns used to encode this information.

Involvement of glucocorticoid-mediated Zn2+ signaling in attenuation of hippocampal CA1 LTP by acute stress

Glucocorticoid–glutamatergic interactions have been proposed as a potential model to explain stress-mediated impairment of cognition. However, it is unknown whether glucocorticoid–zincergic interactions are involved in this impairment. Histochemically reactive zinc (Zn2+) is co-released with glutamate from zincergic neurons. In the present study, involvement of synaptic Zn2+ in stress-induced attenuation of CA1 LTP was examined in hippocampal slices from young rats after exposure to tail suspension stress for 30s, which significantly increased serum corticosterone. Stress-induced attenuation of CA1 LTP was ameliorated by administration of clioquinol, a membrane permeable zinc chelator, to rats prior to exposure to stress, implying that the reduction of synaptic Zn2+ by clioquinol participates in this amelioration. To pursue the involvement of corticosterone-mediated Zn2+ signal in the attenuated CA1 LTP by stress, dynamics of synaptic Zn2+ was checked in hippocampal slices exposed to corticosterone. Corticosterone increased extracellular Zn2+ levels measured with ZnAF-2 dose-dependently, as well as the intracellular Ca2+ levels measured with calcium orange AM, suggesting that corticosterone excites zincergic neurons in the hippocampus and increases Zn2+ release from the neuron terminals. Intracellular Zn2+ levels measured with ZnAF-2DA were also increased dose-dependently, but not in the coexistence of CaEDTA, a membrane-impermeable zinc chelator, suggesting that intracellular Zn2+ levels is increased by the influx of extracellular Zn2+. Furthermore, corticosterone-induced attenuation of CA1 LTP was abolished in the coexistence of CaEDTA. The present study suggests that corticosterone-mediated increase in postsynaptic Zn2+ signal in the cytosolic compartment is involved in the attenuation of CA1 LTP after exposure to acute stress.

Amelioration of social isolation-triggered onset of early Alzheimer's disease-related cognitive deficit by N-acetylcysteine in a transgenic mouse model

Epidemiological study reveals that socially isolated persons have increased risk of developing Alzheimer's disease (AD). Whether this risk arises from an oxidative stress is unclear. Here we show that N-acetylcysteine (NAC), an anti-oxidant, is capable of preventing social isolation-induced accelerated impairment of contextual fear memory and rundown of hippocampal LTP in 3-month old APP/PS1 mice. Increased hippocampal levels of γ-secretase activity, Aβ-40 and Aβ-42 seen in the isolated APP/PS1 mice were reduced by chronic treatment of NAC. In addition, social isolation-induced increase in calpain activity and p25/p35 ratio concomitant with decrease in membrane-associated p35 and p35/Cdk5 activity was normalized by NAC. NAC pretreatment also reversed isolation-induced decrease in GluR1 Ser831 phosphorylation, surface expression of AMPARs and p35–GluR1–CaMKII interactions. These results suggest that NAC decreases γ-secretase activity resulting in the attenuation of Aβ production, calpain activity and conversion of p35 to p25 which stabilized p35–GluR1–CaMKII interactions and restored GluR1 and GluR2 surface expression. Our results indicate that NAC is effective in mouse models of AD and has translation potential for the human disorder.

Hippocampal LTP triggers proteasome‐mediated SPAR degradation in CA1 neurons

Activity-dependent synaptic plasticity is associated with synaptic protein turnover involving the ubiquitin proteasome system (UPS) for protein degradation. In primary hippocampal cell culture, it has been shown that increased or decreased activity of synaptic transmission can regulate the amount of postsynaptic density (PSD) proteins via UPS. However, the specific spatio-temporal dynamic of PSD protein degradation after LTP induction and its downstream signaling pathways remains to be clarify. We used confocal microscopy to monitor levels of eGFP-tagged SPAR (spine-associated Rap GTPase activating protein) expressed in acute hippocampal slices and found that LTP induction triggered a UPS-dependent decay of eGFP-SPAR fluorescence. SPAR degradation was reduced upon inhibition of cyclin-dependent kinase 5 (CDK5) as well as by a protein synthesis inhibitor. Comparison of eGFP-tagged SPAR levels with those obtained in control experiments with eGFP revealed a protein synthesis-independent component of LTP-associated SPAR degradation. This second component required UPS and NMDA receptor activation but not CDK5. We conclude that LTP triggers a down regulation of SPAR by two complementary mechanisms, one of which has previously been described to mediate homeostatic plasticity.

Real-time imaging of proteasome-mediated SPAR degradation in CA1 neurons and its involvement in hippocampal LTP

Real-time imaging of proteasome-mediated SPAR degradation in CA1 neurons and its involvement in hippocampal LTP

Subunit-specific translocation of AMPA Receptors during hippocampal LTP

Subunit-specific translocation of AMPA Receptors during hippocampal LTP

A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density

The A kinase anchor protein AKAP150 recruits the cAMP-dependent protein kinase (PKA) to dendritic spines. Here we show that in AKAP150 (AKAP5) knock-out (KO) mice frequency of miniature excitatory post-synaptic currents (mEPSC) and inhibitory post-synaptic currents (mIPSC) are elevated at 2 weeks and, more modestly, 4 weeks of age in the hippocampal CA1 area versus litter mate WT mice. Linear spine density and ratio of AMPAR to NMDAR EPSC amplitudes were also increased. Amplitude and decay time of mEPSCs, decay time of mIPSCs, and spine size were unaltered. Mice in which the PKA anchoring C-terminal 36 residues of AKAP150 are deleted (D36) showed similar changes. Furthermore, whereas acute stimulation of PKA (2-4 h) increases spine density, prolonged PKA stimulation (48 h) reduces spine density in apical dendrites of CA1 pyramidal neurons in organotypic slice cultures. The data from the AKAP150 mutant mice show that AKAP150-anchored PKA chronically limits the number of spines with functional AMPARs at 2-4 weeks of age. However, synaptic transmission and spine density was normal at 8 weeks in KO and D36 mice. Thus AKAP150-independent mechanisms correct the aberrantly high number of active spines in juvenile AKAP150 KO and D36 mice during development.

The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3 S,4 S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2 H-pyran-4-yl)-1,5-dihydro-4 H-pyrazolo[3,4- d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents

Inhibition of phosphodiesterase 9 (PDE9) has been reported to enhance rodent cognitive function and may represent a potential novel approach to improving cognitive dysfunction in Alzheimer’s disease. PF-04447943, (6-[(3 S,4 S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2 H-pyran-4-yl)-1,5-dihydro-4 H-pyrazolo[3,4- d]pyrimidin-4-one), a recently described PDE9 inhibitor, was found to have high affinity ( Ki of 2.8, 4.5 and 18 nM) for human, rhesus and rat recombinant PDE9 respectively and high selectivity for PDE9 versus PDEs1–8 and 10–11. PF-04447943 significantly increased neurite outgrowth and synapse formation (as indicated by increased synapsin 1 expression) in cultured hippocampal neurons at low (30–100 nM) but not high (300–1000 nM) concentrations. PF-04447943 significantly facilitated hippocampal slice LTP evoked by a weak tetanic stimulus at a concentration of 100 nM but failed to affect response to the weak tetanus at either 30 or 300 nM, or the LTP produced by a theta burst stimulus. Systemic administration of PF-04447943 (1–30 mg/kg p.o.) dose-dependently increased cGMP in the cerebrospinal fluid 30 min after administration indicating target engagement in the CNS of rats. PF-04447943 (1–3 mg/kg p.o.) significantly improved cognitive performance in three rodent cognition assays (mouse Y maze spatial recognition memory model of natural forgetting, mouse social recognition memory model of natural forgetting and rat novel object recognition with a scopolamine deficit). When administered at a dose of 3 mg/kg p.o., which improved performance in novel object recognition, PF-04447943 significantly increased phosphorylated but not total GluR1 expression in rat hippocampal membranes. Collectively these data indicate that PF-04447943 is a potent, selective brain penetrant PDE9 inhibitor that increased indicators of hippocampal synaptic plasticity and improved cognitive function in a variety of cognition models in both rats and mice. Results with PF-04447943 are consistent with previously published findings using a structurally diverse PDE9 inhibitor, BAY73-6199, and further support the suggestion that PDE9 inhibition may represent a novel approach to the palliative remediation of cognitive dysfunction.

Tanshinone IIA attenuates neuronal damage and the impairment of long-term potentiation induced by hydrogen peroxide

Tanshinone IIA (Tan IIA) is one of the key components of Salvia miltiorrhiza Bunge that has been widely used for various cardiovascular and cerebrovascular disorders in Asian countries. Many studies have reported that Tan IIA has antioxidative properties, but whether Tan IIA can rescue neurons from oxidative insult has never been reported. The present study was undertaken to evaluate the possible neuroprotective effects of Tan IIA on hydrogen peroxide (H(2)O(2))-induced oxidative stress in rats. H(2)O(2)-induced cytotoxicity was evaluated by the cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and flow cytometry with PI staining. Calcium imaging experiments were carried out to measure intracellular free calcium concentration. Western blotting was used to determine the expression of Bax and Bcl-2 protein. Electrophysiological studies in hippocampal slices were performed to investigate the effect of Tan IIA on synaptic function and cognitive impairment caused by H(2)O(2). It was found that pretreatment with Tan IIA protected primary rat cortical neurons against H(2)O(2)-induced cytotoxicity. Furthermore, Tan IIA markedly reduced the elevation of [Ca(2+)](i) evoked by H(2)O(2). Western blot analysis indicated that pretreatment with Tan IIA prevented the increase in Bax/Bcl-2 ratio induced by H(2)O(2). In addition, preincubation of Tan IIA 20 min prior to H(2)O(2) exposure could reverse H(2)O(2)-induced hippocampal LTP impairment, but without significant alteration in basal synaptic transmission and LTP induction. These findings demonstrate that Tan IIA might serve as a novel promising therapeutic agent for oxidative stress injury in neurodegenerative diseases.

Rescue of a Dystrophin-like Protein by Exon Skipping In Vivo Restores GABAA-receptor Clustering in the Hippocampus of the mdx Mouse

Dystrophin, the cytoskeletal protein whose defect is responsible for Duchenne muscular dystrophy (DMD), is normally expressed in both muscles and brain. Genetic loss of brain dystrophin in the mdx mouse model of DMD reduces the capacity for type A gamma-aminobutyric acid (GABA(A))-receptor clustering in central inhibitory synapses, which is thought to be a main molecular defect leading to brain and cognitive alterations in this syndrome. U7 small nuclear RNAs modified to encode antisense sequences and expressed from recombinant adeno-associated viral (rAAV) vectors have proven efficient after intramuscular injection to induce skipping of the mutated exon 23 and rescue expression of a functional dystrophin-like product in muscle tissues of mdx mice in vivo. Here, we report that intrahippocampal injection of a single dose of rAAV2/1-U7 can rescue substantial levels of brain dystrophin expression (15-25%) in mdx mice for months. This is sufficient to completely restore GABA(A)-receptor clustering in pyramidal and dendritic layers of CA1 hippocampus, suggesting exon-skipping strategies offer the prospect to investigate and correct both brain and muscle alterations in DMD. This provides new evidence that in the adult brain dystrophin is critical for the control of GABA(A)-receptor clustering, which may have an important role in activity-dependent synaptic plasticity in hippocampal circuits.

Hippocampal phenotypes in kalirin-deficient mice

Regulation of forebrain cellular structure and function by small GTPase pathways is crucial for normal and pathological brain development and function. Kalirin is a brain-specific activator of Rho-like small GTPases implicated in neuropsychiatric disorders. We have recently demonstrated key roles for kalirin in cortical synaptic transmission, dendrite branching, spine density, and working memory. However, little is known about the impact of the complete absence of kalirin on the hippocampus in mice. We thus investigated hippocampal function, structure, and associated behavioral phenotypes in KALRN knockout (KO) mice we have recently generated. Here we show that KALRN KO mice had modest impairments in hippocampal LTP, but normal hippocampal synaptic transmission. In these mice, both context and cue-dependent fear conditioning were impaired. Spine density and dendrite morphology in hippocampal pyramidal neurons were not significantly affected in the KALRN KO mice, but small alterations in the gross morphology of the hippocampus were detected. These data suggest that hippocampal structure and function are more resilient to the complete loss of kalirin, and reveal impairments in fear learning. These studies allow the comparison of the phenotypes of different kalirin mutant mice and shed light on the brain region-specific functions of small GTPase signaling.

Rescue of impaired neurogenesis and attenuation of neuropathology in FAD-linked transgenic mice by environmental factors

While the adult mammalian brain exhibits plasticity throughout life, the extent of plasticity declines significantly with aging. In Alzheimer's disease (AD), an aging-linked progressive neurodegenerative disease characterized by memory impairments and cognitive deterioration, numerous aspects of brain plasticity are impaired. For example, we have recently shown that neurogenesis is significantly impaired in the brains of transgenic mice harboring APPswe/PS1ΔE9. In this study we examined the hypothesis that experience of transgenic mice harboring APPswe/PS1ΔE9 in an enriched environment would enhance brain plasticity, manifested in enhanced neurogenesis and hippocampal learning and reduced neuropathology. Extent of neurogenesis and neuropathology were examined in the brain of young APPswe/PS1ΔE9 mice that experienced environmental enrichment and/or standard housing condition. We show that experience of APPswe/PS1ΔE9 mice in enriched environmental conditions upregulates neural progenitor cell proliferation and neural maturation in the dentate gyrus of the hippocampus. Environmental enrichment also reduced levels of soluble oligomeric beta-amyloid peptides and of hyperphosphorylated tau, the precursors of AD hallmarks. Functionally, environmental enrichment significantly enhanced hippocampal LTP, without notable alternation in basal synaptic transmission. In addition, we also observed upregulation of the main anterograde motor protein, kinesin-1, in the brains of these transgenic mice, suggesting the enhancement of axonal transport. This study shows that environmental experience can enhance neuroplasticity, attenuate pathology and enhance synaptic plasticity in transgenic mouse models of AD. This study establishes the high significance of environmental factors and lifestyle in the development of AD.

Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer's disease by reduction of oxidative stress

This study is to examine if hydrogen-rich saline reduced amyloid β (Aβ) induced neural inflammation, and learning and memory deficits in a rat model. S-D male rats (n=84, 280–330g) were divided into three groups, sham-operated, Aβ1-42 injected and Aβ1-42 plus hydrogen-rich saline-treated animals. Hydrogen-rich saline (5ml/kg, i.p., daily) was injected for 14days after intracerebroventricular injection of Aβ1-42. The levels of MDA, IL-6 and TNF-α were assessed by biochemical and ELISA analysis. Morris Water Maze and open field task were used to assess the memory dysfunction and motor dysfunction, respectively. LTP were used to detect the electrophysiology changes, HNE and GFAP immunohistochemistry were used to assess the oxidative stress and glial cell activation. After Aβ1-42 injection, the levels of MDA, IL-6, and TNF-α were increased in brain tissues and hydrogen-rich saline treatment suppressed MDA, IL-6, and TNF-α concentration. Hydrogen-rich saline treatment improved Morris Water Maze and enhanced LTP in hippocampus blocked by Aβ1-42. Furthermore, hydrogen-rich saline treatment also decreased the immunoreactivitiy of HNE and GFAP in hippocampus induced by Aβ1-42. In conclusion, hydrogen-rich saline prevented Aβ-induced neuroinflammation and oxidative stress, which may contribute to the improvement of memory dysfunction in this rat model.

EIF2α Phosphorylation-Dependent Translation in CA1 Pyramidal Cells Impairs Hippocampal Memory Consolidation without Affecting General Translation

Protein synthesis inhibitor antibiotics are widely used to produce amnesia, and have been recognized to inhibit general or global mRNA translation in the basic translational machinery. For instance, anisomycin interferes with protein synthesis by inhibiting peptidyl transferase or the 80S ribosomal function. Therefore, de novo general or global protein synthesis has been thought to be necessary for long-term memory formation. However, it is unclear which mode of translation-gene-specific translation or general/global translation-is actually crucial for the memory consolidation process in mammalian brains. Here, we generated a conditional transgenic mouse strain in which double-strand RNA-dependent protein kinase (PKR)-mediated phosphorylation of eIF2alpha, a key translation initiation protein, was specifically increased in hippocampal CA1 pyramidal cells by the chemical inducer AP20187. Administration of AP20187 significantly increased activating transcription factor 4 (ATF4) translation and concomitantly suppressed CREB-dependent pathways in CA1 cells; this led to impaired hippocampal late-phase LTP and memory consolidation, with no obvious reduction in general translation. Conversely, inhibition of general translation by low-dose anisomycin failed to block hippocampal-dependent memory consolidation. Together, these results indicated that CA1-restricted genetic manipulation of particular mRNA translations is sufficient to impair the consolidation and that consolidation of memories in CA1 pyramidal cells through eIF2alpha dephosphorylation depends more on transcription/translation of particular genes than on overall levels of general translation. The present study sheds light on the critical importance of gene-specific translations for hippocampal memory consolidation.

Analyzing NMDA and AMPA evoked spike-trains in CA1: GluA1 phosphorylation specific patterns in vivo

Event Abstract Back to Event Analyzing NMDA and AMPA evoked spike-trains in CA1: GluA1 phosphorylation specific patterns in vivo Balázs Barkóczi1*, Gábor Juhász2, Robert Averkin1, Imre Vörös3, Botond Penke1, 2 and Viktor Szegedi1 1 Bay Zoltán Foundation for Applied Research, BAYGEN, Hungary 2 University of Szeged, Department of Medical Chemistry, Faculty of General Medicine, Hungary 3 University of Oxford, St John's College, United Kingdom AMPA and NMDA type glutamate receptors convey fast synaptic transmission in the CNS and mediate various forms of hippocampal plasticity. AMPA receptors comprise four subunits – GluA1, GluA2, GluA3 and GluA4 (or GluR1-4) – that combine to form tetramers. GluA1 is central in synaptic plasticity: disruption of glutamate receptor type 1 causes synaptic alterations and learning/memory deficits in mice. Phosphorylation of serines 831 and 845 in the GluA1 subunit by CaMKII and PKA respectively regulates the ion channel properties and synaptic trafficking of GluR1-containing AMPARs during hippocampal LTP. Moreover, altered phosphorylation pattern of GluA1 was shown in various forms of mental disorders, like addiction, mania and major depressive disorder. Tianeptine, an atypical antidepressant, have been shown to increase the phosphorylation level of GluA1 on the CaMKII and PKA site, resulting in enhanced AMPA-evoked spiking activity in vivo. Here we investigated whether the increased level of GluA1 phosphorylation has a specific “fingerprint” on the AMPA-evoked spiking pattern of single CA1 cell in vivo. AMPA evoked spiking trains were recorded from the CA1 region of chloral-hydrate anaesthetized male rats before and after i.p. Tianeptine application. In another set of experiments, weak and strong AMPA and NMDA-stimulation was applied for evoking spike-trains. By comparing AMPA evoked spike-trains with similar firing rates, we show that the spike-trains recorded after Tianeptine application show characteristic features, distinguishing from spike-trains triggered by strong AMPA stimulation. Despite the similar firing rates, the interspike interval distributions are significantly different among the two groups, showing that neuronal output may differ when new receptors are activated compared to posttranscriptional regulation of previously activated receptors. Furthermore, we also show that NMDA evokes spiking activity with different pattern than AMPA induced spike-trains. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Poster Presentation Topic: Disorders of the nervous system Citation: Barkóczi B, Juhász G, Averkin R, Vörös I, Penke B and Szegedi V (2010). Analyzing NMDA and AMPA evoked spike-trains in CA1: GluA1 phosphorylation specific patterns in vivo. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00025 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 19 Apr 2010; Published Online: 19 Apr 2010. * Correspondence: Balázs Barkóczi, Bay Zoltán Foundation for Applied Research, BAYGEN, Szeged, Hungary, barkoczib@baygen.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Balázs Barkóczi Gábor Juhász Robert Averkin Imre Vörös Botond Penke Viktor Szegedi Google Balázs Barkóczi Gábor Juhász Robert Averkin Imre Vörös Botond Penke Viktor Szegedi Google Scholar Balázs Barkóczi Gábor Juhász Robert Averkin Imre Vörös Botond Penke Viktor Szegedi PubMed Balázs Barkóczi Gábor Juhász Robert Averkin Imre Vörös Botond Penke Viktor Szegedi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Developmental, cellular and molecular neurobiology

The second issue of the 200th volume of Experimental Brain Research is devoted to developmental, cellular and molecular neurobiology. It stands in the long tradition of the Journal, which aims at understanding complex functions of the nervous system from the mechanistic to the behavioral level. One group of papers (Bramham et al. 2010; Reid and Harley 2010; Suge et al. 2010) focuses on the molecular mechanisms of learning and memory, whereas a second group addresses questions of adult neurogenesis (Haas et al. 2010; Colditz et al. 2010) and synaptic maturation (Walz et al. 2010). In the paper by Bramham and colleagues (2010), the role of arc in learning and memory is reviewed. It is pointed out that the transcription of the arc gene depends on changes in neuronal activity patterns. In response to these changes, arc mRNA is transported to the dendrites and locally translated by neurons. Since arc is involved in the regulation of actin dynamics and glutamate receptor traYcking at synapses, arc likely plays a critical role in the protein synthesisdependent modiWcation of activated synapses. Thus, arc could be a key molecule which regulates the transfer of information encoded in the form of neuronal activity into information primarily encoded in the molecular composition and structure of synapses. In addition to the wellknown role of arc in synaptic plasticity, Bramham et al. also discuss a role for arc in the regulation of adult hippocampal neurogenesis. This function of arc remains poorly and incompletely understood, and the mechanistic role of arc in neurogenesis may be distinct from its role in synaptic plasticity. The paper by Reid and Harley (2010) also focuses on the regulation of synaptic plasticity. These authors investigated the role of noradrenergic aVerents from the locus coeruleus in LTP. By stimulating the perforant path and the locus coeruleus, they provide evidence that temporal proximity of locus coeruleus-associated norepinephrine release and perforant path stimulation are required to induce long-term plasticity. In contrast to these papers, which focus on hippocampal LTP, the paper of Suge et al. (2010) investigated a hippocampus-independent form of learning: behavioral imprinting. Using c-fos expression as a marker, they demonstrated that the intermediate and medial mesopallium is involved in this form of learning in the chick. The review by Haas and Frotscher (2010) nicely links to the Wrst group of papers focusing on brain plasticity and memory functions. It addresses the issue, whether adult neurogenesis in the dentate gyrus—which has been introduced as a vital form of neural plasticity in the review of Bramham and co-workers—could be involved in the pathogenesis of temporal lobe epilepsy. In fact, an abnormally spread granule cell layer is frequently seen in the dentate gyrus of patients suVering from temporal lobe epilepsy and it has been speculated that this phenomenon could be caused by an abnormal migration of newly generated granule cells in the adult dentate gyrus. Haas and Frotscher (2010) not only refute this hypothesis using an experimental model of granule cell dispersion, but also provide compelling evidence that granule cell dispersion is, in fact, caused by reelin deWciency. They suggest the following sequence of events: Seizure activity decreases reelin expression in Cajal-Retzius cells in the molecular layer of the dentate gyrus. Since reelin may act as a stop-signal for T. Deller (&) · J. C. Jen Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany e-mail: t.deller@em.uni-frankfurt.de

Differential effects of zinc influx via AMPA/kainate receptor activation on subsequent induction of hippocampal CA1 LTP components

Differential effects of zinc influx via AMPA/kainate receptor activation on subsequent induction of hippocampal CA1 LTP components

A physiological role for amyloid-beta protein:enhancement of learning and memory.

Amyloid-beta protein (Abeta) is well recognized as having a significant role in the pathogenesis of Alzheimer's disease (AD). The reason for the presence of Abeta and its physiological role in non-disease states is not clear. In these studies, low doses of Abeta enhanced memory retention in two memory tasks and enhanced acetylecholine production in the hippocampus in vivo. We then tested whether endogenous Abeta has a role in learning and memory in young, cognitively intact mice by blocking endogenous Abeta in healthy 2-month-old CD-1 mice. Blocking Abeta with antibody to Abeta or DFFVG (which blocks Abeta binding) or decreasing Abeta expression with antisense directed at the Abeta precursor, AbetaPP, all resulted in impaired learning in T-maze foot-shock avoidance. Finally, Abeta 1-42 facilitated induction and maintenance of long term potentiation in hippocampal slices, whereas antibodies to Abeta inhibited hippocampal LTP. In conclusion, these results indicate that in normal healthy young animals the presence of Abeta is important for learning and memory.

MDMA (“ecstasy”) impairs learning in the Morris Water Maze and reduces hippocampal LTP in young rats

3,4-Methylenedioxymethamphetamine (MDMA), an important recreational psychostimulant drug, was examined for its ability to alter visuo-spatial learning and synaptic plasticity. Young rats received MDMA (0.2 and 2 mg/kg s.c.) twice per day for 6 days while their visuo-spatial learning was tested using the Morris Water Maze. After this, animals were sacrificed and LTP induced in hippocampal slices. Visuo-spatial learning was impaired and LTP reduced, both dose-dependently, without changes in serotonin levels or paired-pulse facilitation. We conclude that low, nontoxic doses of MDMA, applied during several days, slow learning by impairing postsynaptic plasticity.

Dysbindin regulates hippocampal LTP by controlling NMDA receptor surface expression

Abnormalities in NMDA receptor (NMDAR) function have been implicated in schizophrenia. Here, we show that dysbindin, a schizophrenia-susceptibility gene widely expressed in the forebrain, controls the surface expression of NMDARs in a subunit-specific manner. Imaging analyses revealed a marked increase in surface NR2A, but not NR2B, in hippocampal neurons derived from dysbindin-null mutant mice (Dys-/-). Exogenous expression of dysbindin reduced NR2A surface expression in both wild-type and Dys-/- neurons. Biotinylation experiments also revealed an increase in surface expression of endogenous NR2A in Dys-/- neurons. Disruption of the dysbindin gene dramatically increased NR2A-mediated synaptic currents, without affecting AMPA receptor currents, in hippocampal CA1 neurons. The Dys-/- hippocampal slices exhibited an enhanced LTP, whereas basal synaptic transmission, presynaptic properties, and LTD were normal. Thus, dysbindin controls hippocampal LTP by selective regulation of the surface expression of NR2A. These results reveal subunit-specific regulation of NMDARs by dysbindin, providing an unexpected link between these two proteins implicated in schizophrenia.