LTP Regulates Burst Initiation and Frequency at Mossy Fiber–Granule Cell Synapses of Rat Cerebellum: Experimental Observations and Theoretical Predictions

Long-term potentiation (LTP) is a synaptic change supposed to provide the cellular basis for learning and memory in brain neuronal circuits. Although specific LTP expression mechanisms could be critical to determine the dynamics of repetitive neurotransmission, this important issue remained largely unexplored. In this paper, we have performed whole cell patch-clamp recordings of mossy fiber–granule cell LTP in acute rat cerebellar slices and studied its computational implications with a mathematical model. During LTP, stimulation with short impulse trains at 100 Hz revealed earlier initiation of granule cell spike bursts and a smaller nonsignificant spike frequency increase. In voltage-clamp recordings, short AMPA excitatory postsynaptic current (EPSC) trains showed short-term facilitation and depression and a sustained component probably generated by spillover. During LTP, facilitation disappeared, depression accelerated, and the sustained current increased. The N-methyl-d-aspartate (NMDA) current also increased. In agreement with a presynaptic expression caused by increased release probability, similar changes were observed by raising extracellular [Ca2+]. A mathematical model of mossy fiber–granule cell neurotransmission showed that increasing release probability efficiently modulated the first-spike delay. Glutamate spillover, by causing tonic NMDA and AMPA receptor activation, accelerated excitatory postsynaptic potential (EPSP) temporal summation and maintained a sustained spike discharge. The effect of increasing neurotransmitter release could not be replicated by increasing receptor conductance, which, like postsynaptic manipulations enhancing intrinsic excitability, proved very effective in raising granule cell output frequency. Independent regulation of spike burst initiation and frequency during LTP may provide mechanisms for temporal recoding and gain control of afferent signals at the input stage of cerebellar cortex.

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How Synaptic Release Probability Shapes Neuronal Transmission: Information-Theoretic Analysis in a Cerebellar Granule Cell

Neural Computation ◽

10.1162/neco_a_00006-arleo ◽

2010 ◽

Vol 22 (8) ◽

pp. 2031-2058 ◽

Cited By ~ 30

Author(s):

Angelo Arleo ◽

Thierry Nieus ◽

Michele Bezzi ◽

Anna D'Errico ◽

Egidio D'Angelo ◽

...

Keyword(s):

Information Transmission ◽

Numerical Simulations ◽

Granule Cell ◽

Mossy Fiber ◽

Dendritic Tree ◽

Long Term Potentiation ◽

Cerebellar Granule Cell ◽

Information Theoretic ◽

Cerebellar Granule ◽

Release Probability

A nerve cell receives multiple inputs from upstream neurons by way of its synapses. Neuron processing functions are thus influenced by changes in the biophysical properties of the synapse, such as long-term potentiation (LTP) or depression (LTD). This observation has opened new perspectives on the biophysical basis of learning and memory, but its quantitative impact on the information transmission of a neuron remains partially elucidated. One major obstacle is the high dimensionality of the neuronal input-output space, which makes it unfeasible to perform a thorough computational analysis of a neuron with multiple synaptic inputs. In this work, information theory was employed to characterize the information transmission of a cerebellar granule cell over a region of its excitatory input space following synaptic changes. Granule cells have a small dendritic tree (on average, they receive only four mossy fiber afferents), which greatly bounds the input combinatorial space, reducing the complexity of information-theoretic calculations. Numerical simulations and LTP experiments quantified how changes in neurotransmitter release probability (p) modulated information transmission of a cerebellar granule cell. Numerical simulations showed that p shaped the neurotransmission landscape in unexpected ways. As p increased, the optimality of the information transmission of most stimuli did not increase strictly monotonically; instead it reached a plateau at intermediate p levels. Furthermore, our results showed that the spatiotemporal characteristics of the inputs determine the effect of p on neurotransmission, thus permitting the selection of distinctive preferred stimuli for different p values. These selective mechanisms may have important consequences on the encoding of cerebellar mossy fiber inputs and the plasticity and computation at the next circuit stage, including the parallel fiber–Purkinje cell synapses.

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Presynaptic Current Changes at the Mossy Fiber–Granule Cell Synapse of Cerebellum During LTP

Journal of Neurophysiology ◽

10.1152/jn.2002.88.2.627 ◽

2002 ◽

Vol 88 (2) ◽

pp. 627-638 ◽

Cited By ~ 36

Author(s):

Arianna Maffei ◽

Francesca Prestori ◽

Paola Rossi ◽

Vanni Taglietti ◽

Egidio D'Angelo

Keyword(s):

Glutamate Receptor ◽

Granule Cell ◽

Mossy Fiber ◽

Long Term Potentiation ◽

Receptor Activation ◽

Presynaptic Terminal ◽

Mammalian Brain ◽

Channel Blockers ◽

Presynaptic Mechanisms ◽

Terminal Excitability

The involvement of presynaptic mechanisms in the expression of long-term potentiation (LTP), an enhancement of synaptic transmission suggested to take part in learning and memory in the mammalian brain, has not been fully clarified. Although evidence for enhanced vesicle cycling has been reported, it is unknown whether presynaptic terminal excitability could change as has been observed in invertebrate synapses. To address this question, we performed extracellular focal recordings in cerebellar slices. The extracellular current consisted of a pre- (P1/N1) and postsynaptic (N2/SN) component. In ∼50% of cases, N1 could be subdivided into N1a and N1b. Whereas N1a was part of the fiber volley (P1/N1a), N1b corresponded to a Ca2+-dependent component accounting for 40–50% of N1, which could be isolated from individual mossy fiber terminals visualized with fast tetramethylindocarbocyanine perchlorate (DiI). The postsynaptic response, given its timing and sensitivity to glutamate receptor antagonists [N2 was blocked by 10 μM [1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium (NBQX) and SN by 100 μM APV +50 μM 7-Cl-kyn], corresponded to granule cell excitation. N2 and SN could be reduced by 1) Ca2+ channel blockers, 2) decreasing the Ca2+ to Mg2+ ratio, 3) paired-pulse stimulation, and 4) adenosine receptor activation. However, only the first two manipulations, which modify Ca2+ influx, were associated with N1(or N1b) reduction. LTP was induced by θ-burst mossy fiber stimulation (8 trains of 10 impulses at 100 Hz separated by 150-ms pauses). Interestingly, during LTP, both N1 (or N1b) and N2/SN persistently increased, whereas P1 (or P1/N1a) did not change. Average changes were N1 = 38.1 ± 31.9, N2 = 49.6 ± 48.8, and SN = 59.1 ± 35.5%. The presynaptic changes were not observed when LTP was prevented by synaptic inhibition, by N-methyl-d-aspartate and metabotropic glutamate receptor blockage, or by protein kinase C blockage. Moreover, the presynaptic changes were sensitive to Ca2+channel blockers (1 mM Ni2+ and 5 μM ω-CTx-MVIIC) and occluded by K+ channel blockers (1 mM tetraethylammmonium). Thus regulation of presynaptic terminal excitability may take part in LTP expression at a central mammalian synapse.

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Metabotropic Glutamate Receptor Antagonist AIDA Blocks Induction of Mossy Fiber-CA3 LTP In Vivo

Journal of Neurophysiology ◽

10.1152/jn.00901.2004 ◽

2005 ◽

Vol 93 (5) ◽

pp. 2668-2673 ◽

Cited By ~ 8

Author(s):

Kenira J. Thompson ◽

Mario L. Mata ◽

James E. Orfila ◽

Edwin J. Barea-Rodriguez ◽

Joe L. Martinez

Keyword(s):

Mossy Fiber ◽

Long Term Potentiation ◽

Initial Slope ◽

Maximal Response ◽

Excitatory Postsynaptic Potential ◽

Sprague Dawley ◽

Metabotropic Glutamate ◽

Term Potentiation

Metabotropic glutamate receptors (mGluR) are implicated in long-term memory storage. mGluR-I and mGluR-II antagonists impede various forms of learning and long-term potentiation (LTP) in animals. Despite the evidence linking mGluR to learning mechanisms, their role in mossy fiber-CA3 long-term potentiation (LTP) is not yet clear. To explain the involvement of mGluR-I in memory mechanisms, we examined the function of the mGluR-I antagonist 1-aminoindan-1, 5-dicarboxylic acid (AIDA) on the induction of mossy fiber-CA3 LTP in vivo in male Sprague Dawley and Fischer 344 (F344) rats. Acute extracellular mossy fiber (MF) responses were evoked by stimulation of the MF bundle and recorded in the stratum lucidum of CA3. The excitatory postsynaptic potential (EPSP) magnitude was measured by using the initial slope of the field EPSP slope measured 2–3 ms after response onset. After collection of baseline MF-CA3 responses at 0.05 Hz, animals received either ((±))-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ( N-methyl-d-aspartate-R antagonist, 10 mg/kg ip), naloxone (opioid-R antagonist, 10 mg/kg ip), or AIDA (mGluR antagonist, 1 mg/kg ip or 37.5 nmol ic). LTP was induced by two 100-Hz trains at the intensity sufficient to evoke 50% of the maximal response. Responses were collected for an additional 1 h. AIDA blocked induction of LTP in the mossy fiber pathway ( P < 0.05) in both strains of rats after systemic and in Sprague Dawley rats after intrahippocampal injection.

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NMDA Receptor-Dependent Metaplasticity by High-Frequency Magnetic Stimulation

Neural Plasticity ◽

10.1155/2014/684238 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Tursonjan Tokay ◽

Timo Kirschstein ◽

Marco Rohde ◽

Volker Zschorlich ◽

Rüdiger Köhling

Keyword(s):

Nmda Receptor ◽

High Frequency ◽

Magnetic Stimulation ◽

Metabotropic Glutamate Receptor ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Receptor Activation ◽

Excitatory Postsynaptic Potential ◽

Metabotropic Glutamate

High-frequency magnetic stimulation (HFMS) can elicit N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) at Schaffer collateral-CA1 pyramidal cell synapses. Here, we investigated the priming effect of HFMS on the subsequent magnitude of electrically induced LTP in the CA1 region of rat hippocampal slices using field excitatory postsynaptic potential (fEPSP) recordings. In control slices, electrical high-frequency conditioning stimulation (CS) could reliably induce LTP. In contrast, the same CS protocol resulted in long-term depression when HFMS was delivered to the slice 30 min prior to the electrical stimulation. HFMS-priming was diminished when applied in the presence of the metabotropic glutamate receptor antagonists (RS)-α-methylserine-O-phosphate (MSOP) and (RS)-α-methyl-4-carboxyphenylglycine (MCPG). Moreover, when HFMS was delivered in the presence of the NMDA receptor-antagonist D-2-amino-5-phosphonovalerate (50 µM), CS-induced electrical LTP was again as high as under control conditions in slices without priming. These results demonstrate that HFMS significantly reduced the propensity of subsequent electrical LTP and show that both metabotropic glutamate and NMDA receptor activation were involved in this form of HFMS-induced metaplasticity.

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Tonic Activation of GABAB Receptors Reduces Release Probability at Inhibitory Connections in the Cerebellar Glomerulus

Journal of Neurophysiology ◽

10.1152/jn.91190.2008 ◽

2009 ◽

Vol 101 (6) ◽

pp. 3089-3099 ◽

Cited By ~ 37

Author(s):

Lisa Mapelli ◽

Paola Rossi ◽

Thierry Nieus ◽

Egidio D'Angelo

Keyword(s):

Neurotransmitter Release ◽

Mossy Fiber ◽

Signal Transmission ◽

Receptor Activation ◽

Gabab Receptors ◽

Dynamic Regulation ◽

Release Probability ◽

Receptor Modulation ◽

Tonic Activation ◽

Ambient Gaba

In the cerebellum, granule cells are inhibited by Golgi cells through GABAergic synapses generating complex responses involving both phasic neurotransmitter release and the establishment of ambient γ-aminobutyric acid (GABA) levels. Although at this synapse the mechanisms of postsynaptic integration have been clarified to a considerable extent, the mechanisms of neurotransmitter release remained largely unknown. Here we have investigated the quantal properties of release during repetitive neurotransmission, revealing that tonic GABAB receptor activation by ambient GABA regulates release probability. Blocking GABAB receptors with CGP55845 enhanced the first inhibitory postsynaptic current (IPSC) and short-term depression in a train while reducing trial-to-trial variability and failures. The changes caused by CGP55845 were similar to those caused by increasing extracellular Ca2+ concentration, in agreement with a presynaptic GABAB receptor modulation of release probability. However, the slow tail following IPSC peak demonstrated a remarkable temporal summation and was not modified by CGP55845 or extracellular Ca2+ increase. This result shows that tonic activation of presynaptic GABAB receptors by ambient GABA selectively regulates the onset of inhibition bearing potential consequences for the dynamic regulation of signal transmission through the mossy fiber–granule cell pathway of the cerebellum.

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Reversible Synaptic Depression in Developing Rat CA3–CA1 Synapses Explained by a Novel Cycle of AMPA Silencing-Unsilencing

Journal of Neurophysiology ◽

10.1152/jn.00602.2007 ◽

2007 ◽

Vol 98 (5) ◽

pp. 2604-2611 ◽

Cited By ~ 19

Author(s):

Therése Abrahamsson ◽

Bengt Gustafsson ◽

Eric Hanse

Keyword(s):

Metabotropic Glutamate Receptor ◽

Low Frequency ◽

Long Term Potentiation ◽

Synaptic Depression ◽

Receptor Activation ◽

Excitatory Postsynaptic Potential ◽

Whole Cell ◽

Metabotropic Glutamate ◽

Silent Synapses ◽

Recording Conditions

In the developing hippocampus, experiments using whole cell recordings have shown that a small number of synaptic activations can convert many glutamate synapses to AMPA silent synapses. This depression of AMPA signaling is induced by low-frequency (0.05–0.2 Hz) activation, does not require N-methyl-d-aspartate or metabotropic glutamate receptor activation for its induction, and does not readily reverse after stimulus interruption. Here we show, using field recordings and perforated patch-clamp recordings of transmission in developing CA3–CA1 synapses, that this synaptic depression also can be observed under more noninvasive recording conditions. Moreover, under these conditions, the synaptic depression spontaneously recovers within 20 min by the absence of synaptic activation alone, with a time constant of ∼7 min as determined by field excitatory postsynaptic potential recordings. Thus as for the expression of long-term potentiation (LTP), recovery from this depression is susceptible to whole cell dialysis (“wash-out”). In contrast to LTP-induced unsilencing, the AMPA signaling after stimulus interruption was again labile, resumed stimulation resulted in renewed depression. The present study has thus identified a novel cycle for AMPA signaling in which the nascent glutamate synapse cycles between an AMPA silent state, induced by a small number of synaptic activations, and a labile AMPA signaling, induced by prolonged inactivity.

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Faculty Opinions recommendation of Stable mossy fiber long-term potentiation requires calcium influx at the granule cell soma, protein synthesis, and microtubule-dependent axonal transport.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5568957.5582057 ◽

2010 ◽

Author(s):

Hilmar Bading ◽

Carlos Bas Orth

Keyword(s):

Protein Synthesis ◽

Axonal Transport ◽

Granule Cell ◽

Mossy Fiber ◽

Calcium Influx ◽

Long Term Potentiation ◽

Cell Soma ◽

Term Potentiation

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Long-Term Potentiation at the Mossy Fiber–Granule Cell Relay Invokes Postsynaptic Second-Messenger Regulation of Kv4 Channels

Journal of Neuroscience ◽

10.1523/jneurosci.2051-16.2016 ◽

2016 ◽

Vol 36 (44) ◽

pp. 11196-11207 ◽

Cited By ~ 7

Author(s):

Arsalan P. Rizwan ◽

Xiaoqin Zhan ◽

Gerald W. Zamponi ◽

Ray W. Turner

Keyword(s):

Granule Cell ◽

Mossy Fiber ◽

Second Messenger ◽

Long Term Potentiation ◽

Term Potentiation ◽

Kv4 Channels

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NMDA-Independent LTP by Adenosine A2 Receptor-Mediated Postsynaptic AMPA Potentiation in Hippocampus

Journal of Neurophysiology ◽

10.1152/jn.1997.78.4.1965 ◽

1997 ◽

Vol 78 (4) ◽

pp. 1965-1972 ◽

Cited By ~ 24

Author(s):

Kofi Kessey ◽

David J. Mogul

Keyword(s):

Synaptic Transmission ◽

Ampa Receptor ◽

Hippocampal Slices ◽

Low Frequency ◽

Long Term Potentiation ◽

Receptor Activation ◽

Common Mechanism ◽

Excitatory Postsynaptic Potential ◽

Ca1 Region ◽

The Brain

Kessey, Kofi and David J. Mogul. NMDA-independent LTP by adenosine A2 receptor-mediated postsynaptic AMPA potentiation in hippocampus. J. Neurophysiol. 78: 1965–1972, 1997. The role of adenosine A2 receptors in normal synaptic transmission and tetanus-induced long-term potentiation (LTP) was tested by stimulation of the Schaffer collateral pathway and recording of the field excitatory postsynaptic potential (EPSP) in the CA1 region of rat transverse hippocampal slices. Activation of adenosine A2 receptors with the A2 agonist N 6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA; 20 nM) enhanced synaptic transmission during low-frequency test pulses (0.033 Hz). Paired stimulation before and during DPMA exposure indicated no paired-pulse facilitation as a result of A2 activation, suggesting that enhancement was not a result of presynaptic modulation. DPMA enhanced the early phase α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) component of the EPSP. In contrast, DPMA had no effect on the N-methyl-d-aspartate (NMDA) component isolated using low extracellular Mg2+ and the AMPA receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (20 μM), indicating that the effects of A2 activation on synaptic transmission were mediated by a postsynaptic enhancement of the AMPA response. Activation of adenosine A2 receptors during a brief tetanus (100 Hz, 1 s) increased the level of LTP by 36% over that seen in response to a tetanus under control conditions. DPMA exposure after prior induction of LTP showed no additional potentiation, indicating that the mechanisms that contribute to both types of increases in synaptic transmission share a common mechanism. A slow onset NMDA-independent LTP could be induced by application of a tetanus during perfusion of DPMA with the NMDA blocker AP5 (50 μM). Blockade of L-type Ca channels with nifedipine (10 μM) had no effect on normal synaptic transmission but reduced NMDA-independent LTP by 32%. Very little NMDA-independent LTP could be induced after prior saturation of NMDA-dependent LTP via multiple tetani spaced 10 min apart, indicating that both forms of LTP are eventually convergent on a common mechanism, presumably the postsynaptic AMPA receptor response. Because extracellular adenosine levels are modulated by cellular activity throughout the brain and because adenosine receptor activation can markedly alter levels of synaptic transmission independent of NMDA receptors, adenosine may play an important and complex role as a modulator of synaptic transmission in the brain.

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