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A Mathematical model for Astrocytes mediated LTP at Single Hippocampal Synapses  [PDF]
Shivendra Tewari,Kaushik Majumdar
Quantitative Biology , 2011, DOI: 10.1007/s10827-012-0389-5
Abstract: Many contemporary studies have shown that astrocytes play a significant role in modulating both short and long form of synaptic plasticity. There are very few experimental models which elucidate the role of astrocyte over Long-term Potentiation (LTP). Recently, Perea & Araque (2007) demonstrated a role of astrocytes in induction of LTP at single hippocampal synapses. They suggested a purely pre-synaptic basis for induction of this N-methyl-D- Aspartate (NMDA) Receptor-independent LTP. Also, the mechanisms underlying this pre-synaptic induction were not investigated. Here, in this article, we propose a mathematical model for astrocyte modulated LTP which successfully emulates the experimental findings of Perea & Araque (2007). Our study suggests the role of retrograde messengers, possibly Nitric Oxide (NO), for this pre-synaptically modulated LTP.
Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo
Ruth Drdla, Jürgen Sandkühler
Molecular Pain , 2008, DOI: 10.1186/1744-8069-4-18
Abstract: LTP at the first synapse in pain pathways is considered to underlie some forms of pain amplification e.g. after trauma, inflammation or nerve injury [1]. A strong rise in postsynaptic calcium ion concentration triggering Ca2+-dependent signal transduction pathways is required for LTP induction [2-4]. Consequently, high-frequency (~100 Hz), burst-like stimulation protocols were previously used to induce LTP at virtually all synapses studied so far.Low-level activity between 1–10 imp·s-1 rather than high frequency bursts are, however, typical for C-fibre discharges during inflammation, trauma or wound healing. Presynaptic activity at these low frequencies is considered inadequate to cause a sufficiently strong rise in postsynaptic [Ca2+]i for potentiation of synaptic strength. In fact, low-level presynaptic activity was either ineffective or induced synaptic long-term depression (LTD) rather than LTP in previous studies.We have recently discovered that in a spinal cord slice preparation with long dorsal roots intact LFS of dorsal roots at C-fibre intensity induces LTP which involves a rise in postsynaptic [Ca2+]i and Ca2+-dependent signal transduction pathways [4]. In the intact animal spinal dorsal neurons are, however, under a powerful tonic inhibition arising from supraspinal, descending pathways [5,6]. This inhibition is inevitably lost in the in vitro situation and could thereby facilitate LTP-induction. And indeed, removal of descending, putatively inhibitory pathways by spinalisation is required for the induction of LTP by either pinching or noxious heating of the skin [7]. On the other hand, we have shown recently that in the intact animal, LTP can be induced by LFS as well as by subcutaneous capsaicin or formalin injections also [4]. Here, we further characterised this novel LFS-induced LTP at C-fibre synapses in the intact animal.After obtaining approval from the Institutional Animal Care Comitee (Austrian Federal Ministry for Education, Science and Culture)
Quantitative Organization of GABAergic Synapses in the Molecular Layer of the Mouse Cerebellar Cortex  [PDF]
Federica Briatore,Annarita Patrizi,Laura Viltono,Marco Sassoè-Pognetto,Peer Wulff
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012119
Abstract: In the cerebellar cortex, interneurons of the molecular layer (stellate and basket cells) provide GABAergic input to Purkinje cells, as well as to each other and possibly to other interneurons. GABAergic inhibition in the molecular layer has mainly been investigated at the interneuron to Purkinje cell synapse. In this study, we used complementary subtractive strategies to quantitatively assess the ratio of GABAergic synapses on Purkinje cell dendrites versus those on interneurons. We generated a mouse model in which the GABAA receptor α1 subunit (GABAARα1) was selectively removed from Purkinje cells using the Cre/loxP system. Deletion of the α1 subunit resulted in a complete loss of GABAAR aggregates from Purkinje cells, allowing us to determine the density of GABAAR clusters in interneurons. In a complementary approach, we determined the density of GABA synapses impinging on Purkinje cells using α-dystroglycan as a specific marker of inhibitory postsynaptic sites. Combining these inverse approaches, we found that synapses received by interneurons represent approximately 40% of all GABAergic synapses in the molecular layer. Notably, this proportion was stable during postnatal development, indicating synchronized synaptogenesis. Based on the pure quantity of GABAergic synapses onto interneurons, we propose that mutual inhibition must play an important, yet largely neglected, computational role in the cerebellar cortex.
Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP  [PDF]
Marco Canepari, Kaspar E. Vogt
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0004011
Abstract: The architecture of parallel fiber axons contacting cerebellar Purkinje neurons retains spatial information over long distances. Parallel fiber synapses can trigger local dendritic calcium spikes, but whether and how this calcium signal leads to plastic changes that decode the parallel fiber input organization is unknown. By combining voltage and calcium imaging, we show that calcium signals, elicited by parallel fiber stimulation and mediated by voltage-gated calcium channels, increase non-linearly during high-frequency bursts of electrically constant calcium spikes, because they locally and transiently saturate the endogenous buffer. We demonstrate that these non-linear calcium signals, independently of NMDA or metabotropic glutamate receptor activation, can induce parallel fiber long-term potentiation. Two-photon imaging in coronal slices revealed that calcium signals inducing long-term potentiation can be observed by stimulating either the parallel fiber or the ascending fiber pathway. We propose that local dendritic calcium spikes, evoked by synaptic potentials, provide a unique mechanism to spatially decode parallel fiber signals into cerebellar circuitry changes.
Age-Induced Loss of Mossy Fibre Synapses on CA3 Thorns in the CA3 Stratum Lucidum  [PDF]
Bunmi Ojo,Heather Davies,Payam Rezaie,Paul Gabbott,Francis Colyer,Igor Kraev,Michael G. Stewart
Neuroscience Journal , 2013, DOI: 10.1155/2013/839535
Abstract: Advanced ageing is associated with hippocampal deterioration and mild cognitive decline. The hippocampal subregion CA3 stratum lucidum (CA3-SL) receives neuronal inputs from the giant mossy fibre boutons of the dentate gyrus, but relatively little is known about the integrity of this synaptic connection with ageing. Using serial electron microscopy and unbiased stereology, we examined age-related changes in mossy fibre synapses on CA3 thorny excrescences within the CA3-SL of young adults (4-month-old), middle-aged (12-month-old), and old-aged (28-month-old) Wistar rats. Our data show that while there is an increase in CA3 volume with ageing, there is a significant (40–45%) reduction in synaptic density within the CA3-SL of 12- and 28-month-old animals compared with 4-month-old animals. We also present preliminary data showing that the CA3 neuropil in advanced ageing was conspicuously full of lipofuscin and phagolysosome positive, activated microglial cellular processes, and altered perivascular pathology. These data suggest that synaptic density in the CA3-SL is significantly impaired in ageing, accompanied by underlying prominent ultrastructural glial and microvascular changes. 1. Introduction Age-related hippocampal deterioration and deficits in cognitive function (spatial memory) [1, 2] are correlated with ultrastructural changes in the CA3 hippocampal subregion, including (i) loss of synapses and integral synaptic proteins (CA3-SR) [3–11], (ii) significant microglia activation [12], (iii) changes in synaptic plasticity [13], and (iv) altered synaptic-glial interactions [9]. The functional integrity of mossy fibre axons whose large giant boutons project to the dendritic spines (thorny excrescences) located in the CA3 stratum lucidum (SL) is essential in both long-term potentiation (LTP) and storage and recall of spatial representation on modifiable synapses of recurrent collaterals of the CA3 pyramidal cells [14]. Electron microscopic studies have reported marked ultrastructural plasticity of synaptic connections in the CA3-SL, in correlation with neurobehavioral performance [4]. Although a large body of data has reported significant age-related ultrastructural changes in the CA3, very little is currently known about the integrity of these mossy fibre synaptic connections in the CA3-SL with advanced ageing. Our aim was to use unbiased stereological methodology to determine whether subtle age-related morphological changes could be demonstrated in the relatively unexplored mossy fibre synapses which form on CA3 thorny excrescences in Wistar rats. The
Persistent Posttetanic Depression at Cerebellar Parallel Fiber to Purkinje Cell Synapses  [PDF]
Astrid Bergerot, Mark Rigby, Guy Bouvier, Pa?kan Marcaggi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070277
Abstract: Plasticity at the cerebellar parallel fiber to Purkinje cell synapse may underlie information processing and motor learning. In vivo, parallel fibers appear to fire in short high frequency bursts likely to activate sparsely distributed synapses over the Purkinje cell dendritic tree. Here, we report that short parallel fiber tetanic stimulation evokes a ~7–15% depression which develops over 2 min and lasts for at least 20 min. In contrast to the concomitantly evoked short-term endocannabinoid-mediated depression, this persistent posttetanic depression (PTD) does not exhibit a dependency on the spatial pattern of synapse activation and is not caused by any detectable change in presynaptic calcium signaling. This persistent PTD is however associated with increased paired-pulse facilitation and coefficient of variation of synaptic responses, suggesting that its expression is presynaptic. The chelation of postsynaptic calcium prevents its induction, suggesting that post- to presynaptic (retrograde) signaling is required. We rule out endocannabinoid signaling since the inhibition of type 1 cannabinoid receptors, monoacylglycerol lipase or vanilloid receptor 1, or incubation with anandamide had no detectable effect. The persistent PTD is maximal in pre-adolescent mice, abolished by adrenergic and dopaminergic receptors block, but unaffected by adrenergic and dopaminergic agonists. Our data unveils a novel form of plasticity at parallel fiber synapses: a persistent PTD induced by physiologically relevant input patterns, age-dependent, and strongly modulated by the monoaminergic system. We further provide evidence supporting that the plasticity mechanism involves retrograde signaling and presynaptic diacylglycerol.
Local Field Potential Modeling Predicts Dense Activation in Cerebellar Granule Cells Clusters under LTP and LTD Control  [PDF]
Shyam Diwakar, Paola Lombardo, Sergio Solinas, Giovanni Naldi, Egidio D'Angelo
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021928
Abstract: Local field-potentials (LFPs) are generated by neuronal ensembles and contain information about the activity of single neurons. Here, the LFPs of the cerebellar granular layer and their changes during long-term synaptic plasticity (LTP and LTD) were recorded in response to punctate facial stimulation in the rat in vivo. The LFP comprised a trigeminal (T) and a cortical (C) wave. T and C, which derived from independent granule cell clusters, co-varied during LTP and LTD. To extract information about the underlying cellular activities, the LFP was reconstructed using a repetitive convolution (ReConv) of the extracellular potential generated by a detailed multicompartmental model of the granule cell. The mossy fiber input patterns were determined using a Blind Source Separation (BSS) algorithm. The major component of the LFP was generated by the granule cell spike Na+ current, which caused a powerful sink in the axon initial segment with the source located in the soma and dendrites. Reproducing the LFP changes observed during LTP and LTD required modifications in both release probability and intrinsic excitability at the mossy fiber-granule cells relay. Synaptic plasticity and Golgi cell feed-forward inhibition proved critical for controlling the percentage of active granule cells, which was 11% in standard conditions but ranged from 3% during LTD to 21% during LTP and raised over 50% when inhibition was reduced. The emerging picture is that of independent (but neighboring) trigeminal and cortical channels, in which synaptic plasticity and feed-forward inhibition effectively regulate the number of discharging granule cells and emitted spikes generating “dense” activity clusters in the cerebellar granular layer.
Reevaluation of the role of parallel fiber synapses in delay eyeblink conditioning in mice using Cbln1 as a tool  [PDF]
Kyoichi Emi,Wataru Kakegawa,Eriko Miura,Aya Ito-Ishida,Kazuhisa Kohda,Michisuke Yuzaki
Frontiers in Neural Circuits , 2013, DOI: 10.3389/fncir.2013.00180
Abstract: The delay eyeblink conditioning (EBC) is a cerebellum-dependent type of associative motor learning. However, the exact roles played by the various cerebellar synapses, as well as the underlying molecular mechanisms, remain to be determined. It is also unclear whether long-term potentiation (LTP) or long-term depression (LTD) at parallel fiber (PF)–Purkinje cell (PC) synapses is involved in EBC. In this study, to clarify the role of PF synapses in the delay EBC, we used mice in which a gene encoding Cbln1 was disrupted (cbln1-/- mice), which display severe reduction of PF–PC synapses. We showed that delay EBC was impaired in cbln1-/- mice. Although PF-LTD was impaired, PF-LTP was normally induced in cbln1-/- mice. A single recombinant Cbln1 injection to the cerebellar cortex in vivo completely, though transiently, restored the morphology and function of PF–PC synapses and delay EBC in cbln1-/- mice. Interestingly, the cbln1-/- mice retained the memory for at least 30 days, after the Cbln1 injection’s effect on PF synapses had abated. Furthermore, delay EBC memory could be extinguished even after the Cbln1 injection’s effect were lost. These results indicate that intact PF–PC synapses and PF-LTD, not PF-LTP, are necessary to acquire delay EBC in mice. In contrast, extracerebellar structures or remaining PF–PC synapses in cbln1-/- mice may be sufficient for the expression, maintenance, and extinction of its memory trace.
VAMP-2, SNAP-25A/B and syntaxin-1 in glutamatergic and GABAergic synapses of the rat cerebellar cortex
Vincenzo Benagiano, Loredana Lorusso, Paolo Flace, Francesco Girolamo, Anna Rizzi, Lorenzo Bosco, Raffaele Cagiano, Beatrice Nico, Domenico Ribatti, Glauco Ambrosi
BMC Neuroscience , 2011, DOI: 10.1186/1471-2202-12-118
Abstract: The examined SNARE proteins were found to be diffusely expressed in glutamatergic synapses, whereas they were rarely observed in GABAergic synapses. However, among glutamatergic synapses, subpopulations which did not contain VAMP-2, SNAP-25A/B and syntaxin-1 were detected. They included virtually all the synapses established by terminals of climbing fibres (immunoreactive for vGluT-2) and some synapses established by terminals of parallel and mossy fibres (immunoreactive for vGluT-1, and for vGluT-1 and 2, respectively). The only GABA synapses expressing the SNARE proteins studied were the synapses established by axon terminals of basket neurons.The present study supplies a detailed morphological description of VAMP-2, SNAP-25A/B and syntaxin-1 in the different types of glutamatergic and GABAergic synapses of the rat cerebellar cortex. The examined SNARE proteins characterize most of glutamatergic synapses and only one type of GABAergic synapses. In the subpopulations of glutamatergic and GABAergic synapses lacking the SNARE protein isoforms examined, alternative mechanisms for regulating trafficking of synaptic vesicles may be hypothesized, possibly mediated by different isoforms or homologous proteins.According to the hypothesis of the soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE), common molecular mechanisms exist in chemical synapses, that regulate the processes of docking, priming and fusion between the synaptic vesicle membrane and specific regions of the plasma membrane (target membrane) and the subsequent release (exocytosis) of neurotransmitters. In the original formulation of the SNARE hypothesis, three proteins were considered, one localized on the vesicle membrane (v-SNARE), synaptobrevin or vesicular associated membrane protein (VAMP), and two localized on the target membrane (t-SNAREs), syntaxin and synaptosomal associated protein of 25 kDa (SNAP-25) [1,2]. When a synaptic site is depolarized, calcium ions penetrate the site and
The NO-cGMP-PKG Signaling Pathway Coordinately Regulates ERK and ERK-Driven Gene Expression at Pre- and Postsynaptic Sites Following LTP-Inducing Stimulation of Thalamo-Amygdala Synapses  [PDF]
Junli Ping,Glenn E. Schafe
Neural Plasticity , 2010, DOI: 10.1155/2010/540940
Abstract: Long-term potentiation (LTP) at thalamic input synapses to the lateral nucleus of the amygdala (LA) has been proposed as a cellular mechanism of the formation of auditory fear memories. We have previously shown that signaling via ERK/MAPK in both the LA and the medial division of the medial geniculate nucleus/posterior intralaminar nucleus (MGm/PIN) is critical for LTP at thalamo-LA synapses. Here, we show that LTP-inducing stimulation of thalamo-LA inputs regulates the activation of ERK and the expression of ERK-driven immediate early genes (IEGs) in both the LA and MGm/PIN. Further, we show that pharmacological blockade of NMDAR-driven synaptic plasticity, NOS activation, or PKG signaling in the LA significantly impairs high-frequency stimulation-(HFS-) induced ERK activation and IEG expression in both regions, while blockade of extracellular NO signaling in the LA impairs HFS-induced ERK activation and IEG expression exclusively in the MGm/PIN. These findings suggest that NMDAR-driven synaptic plasticity and NO-cGMP-PKG signaling within the LA coordinately regulate ERK-driven gene expression in both the LA and the MGm/PIN following LTP induction at thalamo-LA synapses, and that synaptic plasticity in the LA promotes ERK-driven transcription in MGm/PIN neurons via NO-driven “retrograde signaling”. 1. Introduction Fear conditioning is a type of associative learning that is widely studied as a model of learning and memory across a variety of species. Fear conditioning has been extensively characterized at the behavioral level, particularly auditory fear conditioning, in which a tone (CS; conditioned stimulus) is paired with footshock (US; unconditioned stimulus). In brief, auditory fear conditioning is thought to involve transmission and integration of sensory information from CS and US pathways within the lateral nucleus of the amygdala (LA), where alterations in synaptic transmission are believed to encode key aspects of the learning [1–3]. In support of this hypothesis, auditory fear conditioning has been shown to regulate neural activity in the LA; that is, LA neurons respond weakly to a tone CS before conditioning, but respond in a robust manner to the CS after fear conditioning [4, 5]. Long-term potentiation (LTP), an experimental model of synaptic plasticity, is widely believed to be a potential mechanism by which fear conditioning promotes synaptic alterations in the LA [1, 6]. In support of this hypothesis, LTP has been demonstrated in each of the major sensory input pathways that are known to be important for auditory fear conditioning [7–10].
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