Phosphorylation of proteins involved in activity-dependent forms of synaptic plasticity is altered in hippocampal slices maintained in vitro (original) (raw)
Related papers
Role of NMDA Receptor Subtypes in Governing the Direction of Hippocampal Synaptic Plasticity
Science, 2004
Activation of N -methyl- d -aspartate subtype glutamate receptors (NMDARs) is required for long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission at hippocampal CA1 synapses, the proposed cellular substrates of learning and memory. However, little is known about how activation of NMDARs leads to these two opposing forms of synaptic plasticity. Using hippocampal slice preparations, we showed that selectively blocking NMDARs that contain the NR2B subunit abolishes the induction of LTD but not LTP. In contrast, preferential inhibition of NR2A-containing NMDARs prevents the induction of LTP without affecting LTD production. These results demonstrate that distinct NMDAR subunits are critical factors that determine the polarity of synaptic plasticity.
Hippocampus, 2012
Hippocampal synaptic plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) is likely to enable synaptic information storage in support of memory formation. The mouse brain has been subjected to intensive scrutiny in this regard; however, a multitude of studies has examined synaptic plasticity in the hippocampal slice preparation, whereas very few have addressed synaptic plasticity in the freely behaving mouse. Almost nothing is known about the frequency or N-methyl-D-aspartate receptor (NMDAR) dependency of hippocampal synaptic plasticity in the intact mouse brain. Therefore, in this study, we investigated the forms of synaptic plasticity that are elicited at different afferent stimulation frequencies. We also addressed the NMDAR dependency of this phenomenon. Adult male C57BL/6 mice were chronically implanted with a stimulating electrode into the Schaffer collaterals and a recording electrode into the Stratum radiatum of the CA1 region. To examine synaptic plasticity, we chose protocols that were previously shown to produce either LTP or LTD in the hippocampal slice preparation. Low-frequency stimulation (LFS) at 1 Hz (900 pulses) had no effect on evoked responses. LFS at 3 Hz (ranging from 200 up to 2 3 900 pulses) elicited short-term depression (STD, <45 min). LFS at 3 Hz (1,200 pulses) elicited slow-onset potentiation, high-frequency stimulation (HFS) at 100 Hz (100 or 200 pulses) or at 50 Hz was ineffective, whereas 100 Hz (50 pulses) elicited short-term potentiation (STP). HFS at 100 Hz given as 2 3 30, 2 3 50, or 4 3 50 pulses elicited LTP (>24 h). Theta-burst stimulation was ineffective. Antagonism of the NMDAR prevented STD, STP, and LTP. This study shows for the first time that protocols that effectively elicit persistent synaptic plasticity in the slice preparation elicit distinctly different effects in the intact mouse brain. Persistent LTD could not be elicited with any of the protocols tested. Plasticity responses are NMDAR dependent, suggesting that these phenomena are relevant for hippocampus-dependent learning. V V C 2012 Wiley Periodicals, Inc.
Frontiers in Synaptic Neuroscience, 2020
Experience-dependent learning and memory require multiple forms of plasticity at hippocampal and cortical synapses that are regulated by N-methyl-D-aspartate receptors (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)type ionotropic glutamate receptors (NMDAR, AMPAR). These plasticity mechanisms include long-term potentiation (LTP) and depression (LTD), which are Hebbian inputspecific mechanisms that rapidly increase or decrease AMPAR synaptic strength at specific inputs, and homeostatic plasticity that globally scales-up or-down AMPAR synaptic strength across many or even all inputs. Frequently, these changes in synaptic strength are also accompanied by a change in the subunit composition of AMPARs at the synapse due to the trafficking to and from the synapse of receptors lacking GluA2 subunits. These GluA2-lacking receptors are most often GluA1 homomeric receptors that exhibit higher single-channel conductance and are Ca 2+-permeable (CP-AMPAR). This review article will focus on the role of protein phosphorylation in regulation of GluA1 CP-AMPAR recruitment and removal from hippocampal synapses during synaptic plasticity with an emphasis on the crucial role of local signaling by the cAMP-dependent protein kinase (PKA) and the Ca 2+ calmodulin-dependent protein phosphatase 2B/calcineurin (CaN) that is coordinated by the postsynaptic scaffold protein A-kinase anchoring protein 79/150 (AKAP79/150).
Tyrosine phosphorylation-dependent inhibition of hippocampal synaptic plasticity
Neuropharmacology, 2000
We examined the effects of two protein tyrosine phosphatase inhibitors on the induction of synaptic plasticity in CA1 slices of rat hippocampus. Field potential recordings were made in stratum radiatum in response to stimulation of the Schaffer collateral afferents. Bath application of the tyrosine phosphatase inhibitors sodium orthovanadate or phenylarsine oxide for 30 min had little effect on basal synaptic transmission but blocked the induction of both long-term potentiation (LTP) and homosynaptic long-term depression (LTD). LTP could be partially recovered, and LTD fully recovered, when conditioning stimulation was given in conditions of reduced synaptic inhibition. The block of both forms of synaptic plasticity by the phosphatase inhibitors correlated with a concurrent depression of the N-methyl-d-aspartate (NMDA) receptor-mediated potential, as measured both extracellularly and intracellularly. This depression, which was also induced by peroxyvanadate, required synaptic stimulation to be induced, and was tyrosine kinase-dependent. Our results suggest that tyrosine phosphorylation of as yet unidentified proteins is responsible for a novel activity-dependent depression of NMDA receptor function that inhibits synaptic plasticity.
Triggers and substrates of hippocampal synaptic plasticity
Neuroscience & Biobehavioral Reviews, 1991
.--It Is widely assumed that behavioral learmng reflects adaptive properties of the neuronal networks underlying behavior Adaptive properties of networks m turn arise from the existence of biochemical mechamsms that regulate the efficacy of synapnc transmission. Considerable progress has been made in the elucldat~on of the mechamsms revolved m synaptlc plastlc,ty at central synapses and especially those responsible for the phenomenon of long-term potentmtton (LTP) of synapt~c transmission tn hlppocampus Whale the nature and the timing requirements of the mggenng steps are reasonably well "known, there ~s stdl a lot of uncertainty concerning the mechamsms responsible for the long-term changes. Several b~ochermcal processes have been proposed to play critical roles m promoting long-lasting modifications of synapttc efficacy Th~s review examines first the triggers that are necessary to produce LTP in the hippocampus and then the different b~ochemlcal processes that have been considered to partlopate in the maintenance of LTP Finally, we examine the relationships between LTP and behavioral learning Hlppocampus Plasticity Long-term potentmt~on
Journal of Neurophysiology, 2010
N-methyl-d-aspartate (NMDA) receptor-mediated currents are enhanced by phosphorylation. We have investigated effects of phosphorylation-dependent short-term plasticity of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) on the induction of long-term depression (LTD). We confirmed in whole cell clamped CA1 pyramidal neurons that LTD is induced by pairing stimulus protocols. However, after serine-threonine phosphorylation was modified by postsynaptic introduction of a protein phosphatase-1 (PP1) inhibitor, the same pairing protocol evoked long-term potentiation (LTP). We determined effects of modification of phosphatase activity on evoked NMDA EPSCs during LTD induction protocols. During LTD induction, using a protocol pairing depolarization to –40 mV and 0.5 Hz stimulation, NMDA receptor-mediated EPSCs undergo a short-term enhancement at the start of the protocol. In neurons in which PP1 activity was inhibited, this short-term enhancement was markedly amplified. We the...
GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity
Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 2014
N-Methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity is a strong candidate to mediate learning and memory processes that require the hippocampus. This plasticity is bidirectional, and how the same receptor can mediate opposite changes in synaptic weights remains a conundrum. It has been suggested that the NMDAR subunit composition could be involved. Specifically, one subunit composition of NMDARs would be responsible for the induction of long-term potentiation (LTP), whereas NMDARs with a different subunit composition would be engaged in the induction of long-term depression (LTD). Unfortunately, the results from studies that have investigated this hypothesis are contradictory, particularly in relation to LTD. Nevertheless, current evidence does suggest that the GluN2B subunit might be particularly important for plasticity and may make a synapse bidirectionally malleable. In particular, we conclude that the presence of GluN2B subunit-containing NMDARs at the postsynap...
The Journal of Physiology, 2013
• N -Methyl-D-aspartate receptor (NMDAR)-dependent potentiation of synaptic transmission is widely accepted as a cellular model of learning and memory. • It is most often studied in the CA1 area of rat hippocampal slices where it comprises a decremental and a sustained phase, which are commonly referred to as short-term potentiation (STP) and long-term potentiation (LTP), respectively. • In this study we show for the first time that STP and LTP are triggered by the activation of different classes of NMDARs and that STP itself comprises two pharmacologically and kinetically distinct components. • We suggest that the mechanistic separation of STP and LTP is likely to have important functional implications in that these two forms of synaptic plasticity can subserve unique physiological functions in a behaving animal.
Chemical LTD in the CA1 field of the hippocampus from young and mature rats
European Journal of Neuroscience, 1999
Within the hippocampal formation, two forms of long-lasting synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), can be induced which require the activation of NMDA receptors. Interestingly, it has been shown that both LTP and LTD are reduced in adult animals. Recently, a new chemical protocol has been described which elicits LTD in the CA1 ®eld of the hippocampus. Application of 20 mM NMDA for 3 min results in a stable and long-lasting decrease in the evoked synaptic responses. We used this protocol to induce LTD in hippocampal slices from young and adult rats and show that this form of LTD is AP5-sensitive and can be blocked by the protein phosphatase inhibitor cyclosporin A in slices from adult animals. In contrast to electrical LTD (induced by prolonged low frequency stimulation), the extent of chemical LTD was not different between the young and adult rats. These ®ndings indicate that the intracellular signal transduction cascades involved in long-lasting synaptic depression are still intact in adult animals.
Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation
Trends in Neurosciences, 1998
T HE HIPPOCAMPUS is one of a number of brain structures important for the formation of certain kinds of memory 1-3 . Although the information presented to the hippocampal network and that sent on from it to other brain structures remains uncertain, hippocampal neurons exhibit a number of intriguing biophysical properties that enable them to participate in aspects of memory formation. These include synaptic plasticity mechanisms that can respond to incoming information by detecting associative interactions between pre-and post-synaptic activity and register these conjunctions as changes in synaptic weights. Bliss and Lømo 4 gave the first detailed description of the physiological phenomenon now known as LTP that has since become the best studied model of the hypothetical cellular mechanisms of memory formation. Its input specificity, associativity, rapid induction and prolonged duration for hours, days or even weeks (in the intact animal) are all properties that render LTP an attractive model. Distinct forms of LTP have been found in various pathways of the hippocampus and in other structures of the CNS. Of these, associative NMDA-receptor-dependent LTP, which has the above properties, is the most widely studied. Although other forms of lasting synaptic plasticity, such as mossy fibre potentiation, neurotrophin-induced potentiation and LTD are important, we shall hereafter discuss only the NMDA-receptor-dependent form and refer to it, for simplicity, as 'LTP'.