Induction Of Associative Long-term Potentiation Research Articles

Synaptic plasticity at the dentate gyrus granule cell to somatostatin-expressing interneuron synapses supports object location memory.

Somatostatin-expressing interneurons (SOMIs) in the mouse dentate gyrus (DG) receive feedforward excitation from granule cell (GC) mossy fiber (MF) synapses and provide feedback lateral inhibition onto GC dendrites to support environment representation in the DG network. Although this microcircuitry has been implicated in memory formation, little is known about activity-dependent plastic changes at MF-SOMI synapses and their influence on behavior. Here, we report that the metabotropic glutamate receptor 1α (mGluR1α) is required for the induction of associative long-term potentiation (LTP) at MF-SOMI synapses. Pharmacological block of mGluR1α, but not mGluR5, prevented synaptic weight changes. LTP at MF-SOMI synapses was postsynaptically induced, required increased intracellular Ca2+, involved G-protein-mediated and Ca2+-dependent (extracellular signal-regulated kinase) ERK1/2 pathways, and the activation of NMDA receptors. Specific knockdown of mGluR1α in DG-SOMIs by small hairpin RNA expression prevented MF-SOMI LTP, reduced SOMI recruitment, and impaired object location memory. Thus, postsynaptic mGluR1α-mediated MF-plasticity at SOMI input synapses critically supports DG-dependent mnemonic functions.

Alcohol Intoxication by Binge Drinking Impairs Neuroplasticity.

Binge drinking, resulting in acute alcohol intoxication, is considered an initial step in developing alcohol use disorders (AUDs). It has been suggested that alcohol intoxication may act on mechanisms of neuroplasticity to produce brain changes that contribute to the pathophysiology of AUDs. However, the effect of binge drinking on neuroplasticity has not been evaluated in humans. The current study was aimed at evaluating the effect of a binge drinking episode on LTP-like neuroplasticity. In a within-subject randomized, cross-over design, fifteen otherwise healthy binge drinkers were administered paired associative stimulation (PAS) following consumption of alcohol or a placebo beverage. PAS is an experimental paradigm that allows for the induction of associative long-term potentiation (LTP)-like neuroplasticity. Subjects were administered alcohol at a dose of 1.5 g/l of body water, producing a peak blood alcohol concentration (BAC) of 26.1 mM (0.120% BAC). PAS induced neuroplasticity was measured at Post 0 (immediately following PAS), Post 15 (15 minutes following PAS), Post 30 (30 minutes following PAS), Post 60 (60 minutes following PAS) and Post Day 1 (the next day following PAS). The binge drinking episode inhibited LTP-like neuroplasticity, which was significantly different from placebo at 30 and 60 min following the PAS administration. Examination of longitudinal effects revealed no differences between beverages on LTP-like neuroplasticity the following day. Findings suggest that binge drinking impairs neuroplasticity and while these effects are no longer evident the day after a single binge session, repetitive binging may produce long lasting changes in neuroplasticity that contribute to the development of AUDs.

Pull-Push Neuromodulation of LTP and LTD Enables Bidirectional Experience-Induced Synaptic Scaling in Visual Cortex

Neuromodulatory input, acting on G protein-coupled receptors, is essential for the induction of experience-dependent cortical plasticity. Here we report that G-coupled receptors in layer II/III of visual cortex control the polarity of synaptic plasticity through a pull-push regulation of LTP and LTD. In slices, receptors coupled to Gs promote LTP while suppressing LTD; conversely, receptors coupled to Gq11 promote LTD and suppress LTP. In vivo, the selective stimulation of Gs- or Gq11-coupled receptors brings the cortex into LTP-only or LTD-only states, which allows the potentiation or depression of targeted synapses with visual stimulation. The pull-push regulation of LTP/LTD occurs via direct control of the synaptic plasticity machinery and it is independent of changes in NMDAR activation or neuronal excitability. We propose these simple rules governing the pull-push control of LTP/LTD form a general metaplasticity mechanism that may contribute to neuromodulation of plasticity in other cortical circuits.

Kainate Receptors Act as Conditional Amplifiers of Spike Transmission at Hippocampal Mossy Fiber Synapses

Hippocampal mossy fiber (Mf) synapses are viewed as conditional detonators, assisting CA3 cells in complex network functions. By analyzing mice deficient for GluK2 (GluR6), GluK3 (GluR7) and GluK5 (KA2) genes we show that kainate receptors (KARs) play a crucial role in the control of synaptic integration and spike transmission efficacy at Mf synapses. We dissected out the role of the different KAR functions at Mf synapses and we show that presynaptic and postsynaptic KARs concur to amplify unitary Mf synaptic inputs to trigger spike discharge within a wide range of frequencies (from 1 to 50 Hz). Moreover, KARs strongly favor spike transmission in response to patterns of presynaptic activity mimicking in vivo dentate granule cell activity. By amplifying spike transmission, KARs also facilitate the induction of associative long-term potentiation in CA3. Hence the actions of KARs as amplifiers of spike transmission contribute largely to the "conditional detonator" function of Mf synapses and are likely important for spatial information processing.

Synaptic Depolarization Is More Effective than Back-Propagating Action Potentials during Induction of Associative Long-Term Potentiation in Hippocampal Pyramidal Neurons

Long-term potentiation (LTP) requires postsynaptic depolarization that can result from EPSPs paired with action potentials or larger EPSPs that trigger dendritic spikes. We explored the relative contribution of these sources of depolarization to LTP induction during synaptically driven action potential firing in hippocampal CA1 pyramidal neurons. Pairing of a weak test input with a strong input resulted in large LTP (approximately 75% increase) when the weak and strong inputs were both located in the apical dendrites. This form of LTP did not require somatic action potentials. When the strong input was located in the basal dendrites, the resulting LTP was smaller (< or =25% increase). Pairing the test input with somatically evoked action potentials mimicked this form of LTP. Thus, back-propagating action potentials may contribute to modest LTP, but local synaptic depolarization and/or dendritic spikes mediate a stronger form of LTP that requires spatial proximity of the associated synaptic inputs.

Maturation of Long-Term Potentiation Induction Rules in Rodent Hippocampus: Role of GABAergic Inhibition

The induction rules of synaptic plasticity are important for the functional operation of a neural network. We asked whether such synaptic plasticity rules change during development from juvenile to adult animals. Using perforated patch and whole-cell recordings from CA1 pyramidal cells in hippocampal slices, we demonstrate here that the postsynaptic requirements for induction of associative long-term potentiation (LTP) shift gradually. Presynaptic stimulation paired with single postsynaptic action potentials became progressively less effective at inducing LTP with advancing developmental age until, in adult hippocampus, postsynaptic bursts of action potentials were necessary to induce synaptic potentiation. This developmental change might be accounted for by changes in GABA(A) receptor-mediated inhibition known to occur in the hippocampus during this postnatal period, because blocking GABA(A) receptor-mediated inhibition re-established the effectiveness of single postsynaptic action potentials at inducing LTP in adult hippocampus. These data reveal a gradual shift in the induction rules for LTP, explained by a maturational change in GABAergic inhibition, and could have implications for our understanding of the role of inhibition in information processing in the brain.

D-2-Amino-5-phosphonovalerate, an NMDA receptor antagonist, blocks induction of associative long-term potentiation of the flexion reflex in spinal cat

The effect of the NMDA receptor antagonist d-2-amino-5-phosphonovalerate (APV) on classical conditioning of the flexion reflex in spinal cat was examined. Animals perfused intrathecally with artificial cerebral spinal fluid (CSF) containing APV exhibited flexion reflex potentiation during the conditioning period that was not significantly different from cats receiving artificial CSF alone. However, the APV group exhibited no signs of reflex potentiation during the 2.5 h retention period, in contrast to the CSF alone group. The results suggest that NMDA receptor activation plays a critical role in the induction of associative long-term potentiation of flexion reflexes in spinal cat.

Activation of NMDA receptors is necessary for the induction of associative long-term potentiation in area CA1 of the rat hippocampal slice.

1. It is commonly assumed that the role of the strongly activated heterosynaptic input during the induction of associative long-term potentiation (LTP) is to relieve the magnesium blockade of NMDA receptors located at the weakly stimulated synapses and thereby allow the weak input to undergo potentiation. We tested this assumption by using a caged form of the NMDA receptor antagonist, D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) to block the activation of NMDA receptors at the weak input in a conditioning protocol for the induction of associative LTP in area CA1 of the rat hippocampal slice. 2. The effect of releasing D-AP5 by flash photolysis of 100 microM caged D-AP5 (N-[1-(2-nitrophenyl)ethoxycarbonyl]-D-AP5) on pharmacologically isolated NMDA receptor-mediated field EPSPs was examined in area CA1. The slope of the EPSP was reduced by 71% within 50 ms of the initiation of the photolytic reaction when the concentration of released D-AP5 had reached 2.0-2.5 microM and was reduced by 95% within 1 min (10 microM D-AP5 released). 3. Associative LTP was induced by pairing a strong tetanus to one input with a weak tetanus (subthreshold for homosynaptic LTP) to a second input. The strong tetanus preceded the weak by 50 ms. Rapid application of D-AP5, by flash photolysis of caged D-AP5, coincident with the last shock of the strong tetanus, resulted in the blockade of NMDA receptor activation during the period of the weak tetanus. Associative LTP was blocked by photolysis of caged D-AP5 but was normally expressed in experiments using caged L-AP5. 4. We conclude that activation of NMDA receptors at the weakly activated input is an essential requirement for synaptically induced associative LTP.

Sensitivity of Synaptic Plasticity to the Ca2+ Permeability of NMDA Channels: A Model of Long-Term Potentiation in Hippocampal Neurons

We have examined a model by Holmes and Levy (1990) of the induction of associative long-term potentiation (LTP) by a rise in the free Ca2+ concentration ([Ca2+]) after synaptic activation of dendritic spines. The previously reported amplification of the change in [Ca2+] caused by coactivation of several synapses was found to be quite sensitive to changes in the permeability of the N-methyl-D-aspartate (NMDA) receptor channels to Ca2+. Varying this parameter indicated that maximum amplification is obtained at values that are close to Ca2+ permeabilities reported in the literature. However, amplification failed if permeability is reduced by more than 50%. We also found that the maximum free [Ca2+] reached in an individual spine during synaptic coactivation of several spines depended on the location of that spine on the dendritic tree. Distal spines attained a higher [Ca2+] than proximal ones, with differences of up to 80%. The implications of this result for the uniformity of induction of associative LTP in spines in different regions of the dendrite are discussed.

Insights into associative long-term potentiation from computational models of NMDA receptor-mediated calcium influx and intracellular calcium concentration changes

1. Because induction of associative long-term potentiation (LTP) in the dentate gyrus is thought to depend on Ca2+ influx through channels controlled by N-methyl-D-aspartate (NMDA) receptors, quantitative modeling was performed of synaptically mediated Ca2+ influx as a function of synaptic coactivation. The goal was to determine whether Ca2+ influx through NMDA-receptor channels was, by itself, sufficient to explain associative LTP, including control experiments and the temporal requirements of LTP. 2. Ca2+ influx through NMDA-receptor channels was modeled at a synapse on a dendritic spine of a reconstructed hippocampal dentate granule cell when 1-115 synapses on spines at different dendritic locations were activated eight times at frequencies of 10-800 Hz. The resulting change in [Ca2+] in the spine head was estimated from the Ca2+ influx with the use of a model of a dendritic spine that included Ca2+ buffers, pumps, and diffusion. 3. To use a compelling model of synaptic activation, we developed quantitative descriptions of the NMDA and non-NMDA receptor-mediated conductances consistent with available experimental data. The experimental data reported for NMDA and non-NMDA receptor-channel properties and data from other non-LTP experiments that separated the NMDA and non-NMDA receptor-mediated components of synaptic events proved to be limiting for particular synaptic variables. Relative to the non-NMDA glutamate-type receptors, 1) the unbinding of transmitter from NMDA receptors had to be slow, 2) the transition from the bound NMDA receptor-transmitter complex to the open channel state had to be even slower, and 3) the average number of NMDA-receptor channels at a single activated synapse on a single spine head that were open and conducting at a given moment in time had to be very small (usually less than 1). 4. With the use of these quantitative synaptic conductance descriptions. Ca2+ influx through NMDA-receptor channels at a synapse was computed for a variety of conditions. For a constant number of pulses, Ca2+ influx was calculated as a function of input frequency and the number of coactivated synapses. When few synapses were coactivated, Ca2+ influx was small, even for high-frequency activation. However, with larger numbers of coactivated synapses, there was a steep increase in Ca2+ influx with increasing input frequency because of the voltage-dependent nature of the NMDA receptor-mediated conductance. Nevertheless, total Ca2+ influx was never increased more than fourfold by increasing input frequency or the number of coactivated synapses.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuromodulation: Associative and nonlinear adaptation

Neuromodulation, the interaction between at least two chemical messengers in the nervous system, serves as a mechanism by which biochemical association can occur. A simple, yet compelling, hypothesis is that the criteria for expression of associative learning and memory are subserved by biochemical events which are also associative in nature. A neuromodulatory interaction that has been linked to memory function and which has been the subject of biochemical inquiry is the interaction between the catecholamine, norepinephrine (NE) and the neuropeptide, vasopressin (AVP). Studies described in this report show that vasopressin acts to potentiate norepinephrine (NE)-induced cyclic adenosine monophosphate (cAMP) accumulation in the hippocampus by a calcium-dependent mechanism (13). Results of these studies are considered in the context of the nonlinear properties of synergism and conditionality and in the context of the associative learning requirements of spatial and temporal coupling. Secondly, the calcium dependency of AVP-induced neuromodulation is considered in relation to the calcium dependency for induction of associative long-term potentiation. Lastly, the potential for changes in neuronal morphology in response to neuromodulatory events is considered. By using vasopressin potentiation of noradrenalin-induced cAMP formation as a model system, I have applied the theoretical framework of associative learning and memory to test the hypothesis that neuromodulation can serve as a biochemical analog of associative cognitive events.

Influence of picrotoxin and duration of conditioning on the induction of associative long-term potentiation in the mouse hippocampal area CAl in vitro

Field potentials (FP) induced in the radial layer of area CAl by stimulating Schaffer's collaterals (C2) were recorded in murine hippocampal slices and associative long-term potentiation (ALP) produced by combined tetanization of C2 and another group of fibers (C1) was investigated. The effects of simultaneous (C1 and C2) and successive activation (with C1 preceding C2 by 200 msec) of the two inputs were compared. Tetanization preceded by activation of C1 ("conditioning" input) was more effective in experiments with short (30 msec, 100 Hz) trains of stimuli. Tetanization with simultaneous activation of the two inputs as well as tetanization of C1 input by prolonged (150 msec) spike trains with inhibition were blocked by 5·10−6 M picrotoxin. It is suggested that ALP induced by short trains of stimuli succeeding at 200 msec intervals serves as a more suitable model of memory than that induced by prolonged trains (of 1 sec).