scholarly journals Calcium channel-dependent induction of long-term synaptic plasticity at excitatory Golgi cell synapses of cerebellum

2019 ◽  
Author(s):  
F. Locatelli ◽  
T. Soda ◽  
I. Montagna ◽  
S. Tritto ◽  
L. Botta ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Granular Layer ◽  
Voltage Dependence ◽  
Mossy Fiber ◽  
Excitatory Synapses ◽  
Golgi Cell ◽  
Golgi Cells ◽  
Channel Dependent

AbstractThe Golgi cells, together with granule cells and mossy fibers, form a neuronal microcircuit regulating information transfer at the cerebellum input stage. Despite theoretical predictions, little was known about long-term synaptic plasticity at Golgi cell synapses. Here we have used whole-cell patch-clamp recordings and calcium imaging to investigate long-term synaptic plasticity at excitatory synapses impinging on Golgi cells. In acute mouse cerebellar slices, mossy fiber theta-burst stimulation (TBS) could induce either long-term potentiation (LTP) or long-term depression (LTD) at mossy fiber-Golgi cell and granule cell-Golgi cell synapses. This synaptic plasticity showed a peculiar voltage-dependence, with LTD or LTP being favored when TBS induction occurred at depolarized or hyperpolarized potentials, respectively. LTP required, in addition to NMDA channels, activation of T-type Ca2+ channels, while LTD required uniquely activation of L-type Ca2+ channels. Notably, the voltage-dependence of plasticity at the mossy fiber-Golgi cell synapses was inverted with respect to pure NMDA receptor-dependent plasticity at the neighboring mossy fiber-granule cell synapse, implying that the mossy fiber presynaptic terminal can activate different induction mechanisms depending on the target cell. In aggregate, this result shows that Golgi cells show cell-specific forms of long-term plasticity at their excitatory synapses, that could play a crucial role in sculpting the response patterns of the cerebellar granular layer.Significance statementThis paper shows for the first time a novel form of Ca2+ channel-dependent synaptic plasticity at the excitatory synapses impinging on cerebellar Golgi cells. This plasticity is bidirectional and inverted with respect to NMDA receptor-dependent paradigms, with LTD and LTP being favored at depolarized and hyperpolarized potentials, respectively. Furthermore, LTP and LTD induction requires differential involvement of T-ype and L-type voltage-gated Ca2+channels rather than the NMDA receptors alone. These results, along with recent computational predictions, support the idea that Golgi cell plasticity could play a crucial role in controlling information flow through the granular layer along with cerebellar learning and memory.

Evidence for NMDA and mGlu Receptor-Dependent Long-Term Potentiation of Mossy Fiber–Granule Cell Transmission in Rat Cerebellum

1999 ◽  
Vol 81 (1) ◽  
pp. 277-287 ◽  
Author(s):  
Egidio D'Angelo ◽  
Paola Rossi ◽  
Simona Armano ◽  
Vanni Taglietti
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Granule Cell ◽  
High Frequency ◽  
Mossy Fiber ◽  
Long Term Potentiation ◽  
Mglu Receptor ◽  
Rat Cerebellum ◽  
Term Potentiation

D'Angelo, Egidio, Paola Rossi, Simona Armano, and Vanni Taglietti. Evidence for NMDA and mGlu receptor-dependent long-term potentiation of mossy fiber–granule cell transmission in rat cerebellum. J. Neurophysiol. 81: 277–287, 1999. Long-term potentiation (LTP) is a form of synaptic plasticity that can be revealed at numerous hippocampal and neocortical synapses following high-frequency activation of N-methyl-d-aspartate (NMDA) receptors. However, it was not known whether LTP could be induced at the mossy fiber–granule cell relay of cerebellum. This is a particularly interesting issue because theories of the cerebellum do not consider or even explicitly negate the existence of mossy fiber–granule cell synaptic plasticity. Here we show that high-frequency mossy fiber stimulation paired with granule cell membrane depolarization (−40 mV) leads to LTP of granule cell excitatory postsynaptic currents (EPSCs). Pairing with a relatively hyperpolarized potential (−60 mV) or in the presence of NMDA receptor blockers [5-amino-d-phosphonovaleric acid (APV) and 7-chloro-kynurenic acid (7-Cl-Kyn)] prevented LTP, suggesting that the induction process involves a voltage-dependent NMDA receptor activation. Metabotropic glutamate receptors were also involved because blocking them with (+)-α-methyl-4-carboxyphenyl-glycine (MCPG) prevented potentiation. At the cytoplasmic level, EPSC potentiation required a Ca2+ increase and protein kinase C (PKC) activation. Potentiation was expressed through an increase in both the NMDA and non-NMDA receptor-mediated current and by an NMDA current slowdown, suggesting that complex mechanisms control synaptic efficacy during LTP. LTP at the mossy fiber–granule cell synapse provides the cerebellar network with a large reservoir for memory storage, which may be needed to optimize pattern recognition and, ultimately, cerebellar learning and computation.

Synchronization of Golgi and Granule Cell Firing in a Detailed Network Model of the Cerebellar Granule Cell Layer

1998 ◽  
Vol 80 (5) ◽  
pp. 2521-2537 ◽  
Author(s):  
Reinoud Maex ◽  
Erik De Schutter
Keyword(s):  
Granule Cell ◽  
Granular Layer ◽  
Granule Cells ◽  
Cell Layer ◽  
Mossy Fiber ◽  
Parallel Fiber ◽  
Granule Cell Layer ◽  
Golgi Cell ◽  
Golgi Cells ◽  
Cell Firing

Maex, Reinoud and Erik De Schutter. Synchronization of Golgi and granule cell firing in a detailed network model of the cerebellar granule cell layer. J. Neurophysiol. 80: 2521–2537, 1998. The granular layer of the cerebellum has a disproportionately large number of excitatory (granule cells) versus inhibitory neurons (Golgi cells). Its synaptic organization is also unique with a dense reciprocal innervation between granule and Golgi cells but without synaptic contacts among the neurons of either population. Physiological recordings of granule or Golgi cell activity are scarce, and our current thinking about the way the granular layer functions is based almost exclusively on theoretical considerations. We computed the steady-state activity of a large-scale model of the granular layer of the rat cerebellum. Within a few tens of milliseconds after the start of random mossy fiber input, the populations of Golgi and granule cells became entrained in a single synchronous oscillation, the basic frequency of which ranged from 10 to 40 Hz depending on the average rate of firing in the mossy fiber population. The long parallel fibers ensured, through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-mediated synapses, a coherent excitation of Golgi cells, while the regular firing of each Golgi cell synchronized all granule cells within its axonal radius through transient activation of their γ-aminobutyric acid-A (GABAA) receptor synapses. Individual granule cells often remained silent during a few successive oscillation cycles so that their average firing rates, which could be quite variable, reflected the average activities of their mossy fiber afferents. The synchronous, rhythmic firing pattern was robust over a broad range of biologically realistic parameter values and to parameter randomization. Three conditions, however, made the oscillations more transient and could desynchronize the entire network in the end: a very low mossy fiber activity, a very dominant excitation of Golgi cells through mossy fiber synapses (rather than through parallel fiber synapses), and a tonic activation of granule cell GABAA receptors (with an almost complete absence of synaptically induced inhibitory postsynaptic currents). These three conditions were associated with a reduction in the parallel fiber activity, and synchrony could be restored by increasing the mossy fiber firing rate. The model predicts that, under conditions of strong mossy fiber input to the cerebellum, Golgi cells do not only control the strength of parallel fiber activity but also the timing of the individual spikes. Provided that their parallel fiber synapses constitute an important source of excitation, Golgi cells fire rhythmically and synchronized with granule cells over large distances along the parallel fiber axis. According to the model, the granular layer of the cerebellum is desynchronized when the mossy fiber firing rate is low.

scholarly journals Calcium channel-dependent induction of long-term synaptic plasticity at excitatory Golgi cell synapses of cerebellum

2021 ◽  
pp. JN-RM-3013-19
Author(s):  
F. Locatelli ◽  
T. Soda ◽  
I. Montagna ◽  
S. Tritto ◽  
L. Botta ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Calcium Channel ◽  
Golgi Cell ◽  
Channel Dependent

scholarly journals Tactile Stimulation Evokes Long-Term Synaptic Plasticity in the Granular Layer of Cerebellum

2008 ◽  
Vol 28 (25) ◽  
pp. 6354-6359 ◽  
Author(s):  
L. Roggeri ◽  
B. Rivieccio ◽  
P. Rossi ◽  
E. D'Angelo
Keyword(s):  
Synaptic Plasticity ◽  
Tactile Stimulation ◽  
Granular Layer

scholarly journals Chemical LTD, but not LTP, induces transient accumulation of gelsolin in dendritic spines

2019 ◽  
Vol 400 (9) ◽  
pp. 1129-1139 ◽  
Author(s):  
Iryna Hlushchenko ◽  
Pirta Hotulainen
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Long Term Potentiation ◽  
Excitatory Synapses ◽  
Signal Molecule ◽  
Brain Functions ◽  
Dendritic Shaft ◽  
Term Potentiation

Abstract Synaptic plasticity underlies central brain functions, such as learning. Ca2+ signaling is involved in both strengthening and weakening of synapses, but it is still unclear how one signal molecule can induce two opposite outcomes. By identifying molecules, which can distinguish between signaling leading to weakening or strengthening, we can improve our understanding of how synaptic plasticity is regulated. Here, we tested gelsolin’s response to the induction of chemical long-term potentiation (cLTP) or long-term depression (cLTD) in cultured rat hippocampal neurons. We show that gelsolin relocates from the dendritic shaft to dendritic spines upon cLTD induction while it did not show any relocalization upon cLTP induction. Dendritic spines are small actin-rich protrusions on dendrites, where LTD/LTP-responsive excitatory synapses are located. We propose that the LTD-induced modest – but relatively long-lasting – elevation of Ca2+ concentration increases the affinity of gelsolin to F-actin. As F-actin is enriched in dendritic spines, it is probable that increased affinity to F-actin induces the relocalization of gelsolin.

scholarly journals (2S,6S)- and (2R,6R)-hydroxynorketamine inhibit the induction of NMDA receptor-dependent LTP at hippocampal CA1 synapses in mice

2020 ◽  
Vol 4 ◽  
pp. 239821282095784
Author(s):  
Heather Kang ◽  
Pojeong Park ◽  
Muchun Han ◽  
Patrick Tidball ◽  
John Georgiou ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Long Term Potentiation ◽  
Aspartate Receptor ◽  
Term Potentiation ◽  
Hippocampal Ca1 ◽  
Mouse Hippocampus ◽  
Site Of Action ◽  
A Site

The ketamine metabolite (2 R,6 R)-hydroxynorketamine has been proposed to have rapid and persistent antidepressant actions in rodents, but its mechanism of action is controversial. We have compared the ability of ( R,S)-ketamine with the (2 S,6 S)- and (2 R,6 R)-isomers of hydroxynorketamine to affect the induction of N-methyl-d-aspartate receptor–dependent long-term potentiation in the mouse hippocampus. Following pre-incubation of these compounds, we observed a concentration-dependent (1–10 μM) inhibition of long-term potentiation by ketamine and a similar effect of (2 S,6 S)-hydroxynorketamine. At a concentration of 10 μM, (2 R,6 R)-hydroxynorketamine also inhibited the induction of long-term potentiation. These findings raise the possibility that inhibition of N-methyl-d-aspartate receptor–mediated synaptic plasticity is a site of action of the hydroxynorketamine metabolites with respect to their rapid and long-lasting antidepressant-like effects.

scholarly journals Non-synaptic signaling from cerebellar climbing fibers modulates Golgi cell activity

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Angela K Nietz ◽  
Jada H Vaden ◽  
Luke T Coddington ◽  
Linda Overstreet-Wadiche ◽  
Jacques I Wadiche
Keyword(s):  
Feedback Inhibition ◽  
Mossy Fiber ◽  
Molecular Layer ◽  
Cell Activity ◽  
Climbing Fiber ◽  
Climbing Fibers ◽  
In Vivo Studies ◽  
Golgi Cell ◽  
Golgi Cells ◽  
Fiber Stimulation

Golgi cells are the principal inhibitory neurons at the input stage of the cerebellum, providing feedforward and feedback inhibition through mossy fiber and parallel fiber synapses. In vivo studies have shown that Golgi cell activity is regulated by climbing fiber stimulation, yet there is little functional or anatomical evidence for synapses between climbing fibers and Golgi cells. Here, we show that glutamate released from climbing fibers activates ionotropic and metabotropic receptors on Golgi cells through spillover-mediated transmission. The interplay of excitatory and inhibitory conductances provides flexible control over Golgi cell spiking, allowing either excitation or a biphasic sequence of excitation and inhibition following single climbing fiber stimulation. Together with prior studies of spillover transmission to molecular layer interneurons, these results reveal that climbing fibers exert control over inhibition at both the input and output layers of the cerebellar cortex.

scholarly journals Heterosynaptic GABAergic plasticity bidirectionally driven by the activity of pre- and postsynaptic NMDA receptors

2016 ◽  
Vol 113 (35) ◽  
pp. 9898-9903 ◽  
Author(s):  
Jonathan Mapelli ◽  
Daniela Gandolfi ◽  
Antonietta Vilella ◽  
Michele Zoli ◽  
Albertino Bigiani
Keyword(s):  
Nmda Receptor ◽  
Granule Cells ◽  
Dynamic Control ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Golgi Cells ◽  
Neural Information

Dynamic changes of the strength of inhibitory synapses play a crucial role in processing neural information and in balancing network activity. Here, we report that the efficacy of GABAergic connections between Golgi cells and granule cells in the cerebellum is persistently altered by the activity of glutamatergic synapses. This form of plasticity is heterosynaptic and is expressed as an increase (long-term potentiation, LTPGABA) or a decrease (long-term depression, LTDGABA) of neurotransmitter release. LTPGABA is induced by postsynaptic NMDA receptor activation, leading to calcium increase and retrograde diffusion of nitric oxide, whereas LTDGABA depends on presynaptic NMDA receptor opening. The sign of plasticity is determined by the activation state of target granule and Golgi cells during the induction processes. By controlling the timing of spikes emitted by granule cells, this form of bidirectional plasticity provides a dynamic control of the granular layer encoding capacity.

Molecular mechanism linking BDNF/TrkB signaling with the NMDA receptor in memory: the role of Girdin in the CNS

2016 ◽  
Vol 27 (5) ◽  
pp. 481-490 ◽  
Author(s):  
Norimichi Itoh ◽  
Atsushi Enomoto ◽  
Taku Nagai ◽  
Masahide Takahashi ◽  
Kiyofumi Yamada
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Learning And Memory ◽  
Molecular Mechanism ◽  
Neuronal Migration ◽  
Neuronal Development ◽  
Long Term Potentiation ◽  
Long Term Memory ◽  
Tropomyosin Related Kinase B

AbstractIt is well known that synaptic plasticity is the cellular mechanism underlying learning and memory. Activity-dependent synaptic changes in electrical properties and morphology, including synaptogenesis, lead to alterations of synaptic strength, which is associated with long-term potentiation (LTP). Brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling is involved in learning and memory formation by regulating synaptic plasticity. The phosphatidylinositol 3-kinase (PI3-K)/Akt pathway is one of the key signaling cascades downstream BDNF/TrkB and is believed to modulate N-methyl-d-aspartate (NMDA) receptor-mediated synaptic plasticity. However, the molecular mechanism underlying the connection between these two key players in synaptic plasticity remains largely unknown. Girders of actin filament (Girdin), an Akt substrate that directly binds to actin filaments, has been shown to play a role in neuronal migration and neuronal development. Recently, we identified Girdin as a key molecule involved in regulating long-term memory. It was demonstrated that phosphorylation of Girdin by Akt contributed to the maintenance of LTP by linking the BDNF/TrkB signaling pathway with NMDA receptor activity. These findings indicate that Girdin plays a pivotal role in a variety of processes in the CNS. Here, we review recent advances in our understanding about the roles of Girdin in the CNS and focus particularly on neuronal migration and memory.

scholarly journals Hippocampal Somatostatin Interneurons, Long-Term Synaptic Plasticity and Memory

2021 ◽  
Vol 15 ◽  
Author(s):  
Eve Honoré ◽  
Abdessattar Khlaifia ◽  
Anthony Bosson ◽  
Jean-Claude Lacaille
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Inhibitory Neurons ◽  
Inhibitory Interneurons ◽  
Excitatory Synapses ◽  
Dynamic Regulation ◽  
Hippocampal Network ◽  
Hippocampal Networks ◽  
Hippocampal Structure

A distinctive feature of the hippocampal structure is the diversity of inhibitory interneurons. These complex inhibitory interconnections largely contribute to the tight modulation of hippocampal circuitry, as well as to the formation and coordination of neuronal assemblies underlying learning and memory. Inhibitory interneurons provide more than a simple transitory inhibition of hippocampal principal cells (PCs). The synaptic plasticity of inhibitory neurons provides long-lasting changes in the hippocampal network and is a key component of memory formation. The dendrite targeting interneurons expressing the peptide somatostatin (SOM) are particularly interesting in this regard because they display unique long-lasting synaptic changes leading to metaplastic regulation of hippocampal networks. In this article, we examine the actions of the neuropeptide SOM on hippocampal cells, synaptic plasticity, learning, and memory. We address the different subtypes of hippocampal SOM interneurons. We describe the long-term synaptic plasticity that takes place at the excitatory synapses of SOM interneurons, its singular induction and expression mechanisms, as well as the consequences of these changes on the hippocampal network, learning, and memory. We also review evidence that astrocytes provide cell-specific dynamic regulation of inhibition of PC dendrites by SOM interneurons. Finally, we cover how, in mouse models of Alzheimer’s disease (AD), dysfunction of plasticity of SOM interneuron excitatory synapses may also contribute to cognitive impairments in brain disorders.

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