Long-term Depression Of Synaptic Strength Research Articles

Opioids Induce Bidirectional Synaptic Plasticity in a Brainstem Pain Center in the Rat

Opioids are powerful analgesics commonly used in pain management. However, opioids can induce complex neuroadaptations, including synaptic plasticity, that ultimately drive severe side effects, such as pain hypersensitivity and strong aversion during prolonged administration or upon drug withdrawal, even following a single, brief administration. The lateral parabrachial nucleus (LPBN) in the brainstem plays a key role in pain and emotional processing; yet, the effects of opioids on synaptic plasticity in this area remain unexplored. Using patch-clamp recordings in acute brainstem slices from male and female Sprague Dawley rats, we demonstrate a concentration-dependent, bimodal effect of opioids on excitatory synaptic transmission in the LPBN. While a lower concentration of DAMGO (0.5 µM) induced a long-term depression of synaptic strength (low-DAMGO LTD), abrupt termination of a higher concentration (10 µM) induced a long-term potentiation (high-DAMGO LTP) in a subpopulation of cells. LTD involved a metabotropic glutamate receptor (mGluR)-dependent mechanism; in contrast, LTP required astrocytes and N-methyl-D-aspartate receptor (NMDAR) activation. Selective optogenetic activation of spinal and periaqueductal gray matter (PAG) inputs to the LPBN revealed that, while LTD was expressed at all parabrachial synapses tested, LTP was restricted to spino-parabrachial synapses. Thus, we uncovered previously unknown forms of opioid-induced long-term plasticity in the parabrachial nucleus that potentially modulate some adverse effects of opioids. PerspectiveWe found a previously unrecognized site of opioid-induced plasticity in the lateral parabrachial nucleus, a key region for pain and emotional processing. Unraveling opioid-induced adaptations in parabrachial function might facilitate the identification of new therapeutic measures for addressing adverse effects of opioid discontinuation such as hyperalgesia and aversion.

Effect of spike-timing-dependent plasticity on stochastic burst synchronization in a scale-free neuronal network.

We consider an excitatory population of subthreshold Izhikevich neurons which cannot fire spontaneously without noise. As the coupling strength passes a threshold, individual neurons exhibit noise-induced burstings. This neuronal population has adaptive dynamic synaptic strengths governed by the spike-timing-dependent plasticity (STDP). However, STDP was not considered in previous works on stochastic burst synchronization (SBS) between noise-induced burstings of sub-threshold neurons. Here, we study the effect of additive STDP on SBS by varying the noise intensity D in the Barabási-Albert scale-free network (SFN). One of our main findings is a Matthew effect in synaptic plasticity which occurs due to a positive feedback process. Good burst synchronization (with higher bursting measure) gets better via long-term potentiation (LTP) of synaptic strengths, while bad burst synchronization (with lower bursting measure) gets worse via long-term depression (LTD). Consequently, a step-like rapid transition to SBS occurs by changing D, in contrast to a relatively smooth transition in the absence of STDP. We also investigate the effects of network architecture on SBS by varying the symmetric attachment degree [Formula: see text] and the asymmetry parameter [Formula: see text] in the SFN, and Matthew effects are also found to occur by varying [Formula: see text] and [Formula: see text]. Furthermore, emergences of LTP and LTD of synaptic strengths are investigated in details via our own microscopic methods based on both the distributions of time delays between the burst onset times of the pre- and the post-synaptic neurons and the pair-correlations between the pre- and the post-synaptic instantaneous individual burst rates (IIBRs). Finally, a multiplicative STDP case (depending on states) with soft bounds is also investigated in comparison with the additive STDP case (independent of states) with hard bounds. Due to the soft bounds, a Matthew effect with some quantitative differences is also found to occur for the case of multiplicative STDP.

Stochastic spike synchronization in a small-world neural network with spike-timing-dependent plasticity

We consider the Watts–Strogatz small-world network (SWN) consisting of subthreshold neurons which exhibit noise-induced spikings. This neuronal network has adaptive dynamic synaptic strengths governed by the spike-timing-dependent plasticity (STDP). In previous works without STDP, stochastic spike synchronization (SSS) between noise-induced spikings of subthreshold neurons was found to occur in a range of intermediate noise intensities. Here, we investigate the effect of additive STDP on the SSS by varying the noise intensity. Occurrence of a “Matthew” effect in synaptic plasticity is found due to a positive feedback process. As a result, good synchronization gets better via long-term potentiation of synaptic strengths, while bad synchronization gets worse via long-term depression. Emergences of long-term potentiation and long-term depression of synaptic strengths are intensively investigated via microscopic studies based on the pair-correlations between the pre- and the post-synaptic IISRs (instantaneous individual spike rates) as well as the distributions of time delays between the pre- and the post-synaptic spike times. Furthermore, the effects of multiplicative STDP (which depends on states) on the SSS are studied and discussed in comparison with the case of additive STDP (independent of states). These effects of STDP on the SSS in the SWN are also compared with those in the regular lattice and the random graph.

Necessary, but not sufficient: Insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures

Using the rat model of early life seizures (ELS), which has exaggerated mGluR mediated long-term depression of synaptic strength (mGluR-LTD) in adulthood, we probed the signaling cascades underlying mGluR-LTD induction. Several inhibitors completely blocked mGluR-LTD in control but not in ELS rats: the proteasome, the mammalian target of rapamycin (mTOR), S6 kinase (S6K), or L-type voltage-gated calcium channels (L-type VGCC). Inhibition of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) resulted in a near complete block of mGluR-LTD in control rats and a slight reduction of mGluR-LTD in ELS rats. “Autonomous” CaMKII was found to be upregulated in ELS rats, while elevated S6K activity, which is stimulated by mTOR, was described previously. Thus, modulation of each of these factors was necessary for mGluR-LTD induction in control rats, but even their combined, permanent activation in the ELS rats was not sufficient to individually support mGluR-LTD induction following ELS. This implies that while these factors may act sequentially in controls to mediate mGluR-LTD, this is no longer the case after ELS. In contrast, activated ERK was found to be significantly down-regulated in ELS rats. Inhibition of MEK/ERK activation in control rats elevated mGluR-LTD to the exaggerated levels seen in ELS rats. Together, these results elucidate both the mechanisms that persistently enhance mGluR-LTD after ELS and the mechanisms underlying normal mGluR-LTD by providing evidence for multiple, convergent pathways that mediate mGluR-LTD induction. With our prior work, this ties these signaling cascades to the ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization.

Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step

Endocannabinoids (eCBs) mediate short- and long-term depression of synaptic strength by retrograde transsynaptic signaling. Previous studies have suggested that an eCB mobilization or release step in the postsynaptic neuron is involved in this retrograde signaling. However, it is not known whether this release process occurs automatically upon eCB synthesis or whether it is regulated by other synaptic factors. To address this issue, we loaded postsynaptic striatal medium spiny neurons (MSNs) with the eCBs anandamide (AEA) or 2-arachidonoylglycerol and determined the conditions necessary for presynaptic inhibition. We found that presynaptic depression of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) induced by postsynaptic eCB loading required a certain level of afferent activation that varied between the different synaptic types. Synaptic depression at excitatory synapses was temperature-dependent and blocked by the eCB membrane transport blockers, VDM11 and UCM707, but did not require activation of metabotropic glutamate receptors, l-calcium channels, nitric oxide, voltage-activated Na(+) channels, or intracellular calcium. Application of the CB(1)R antagonist, AM251, after depression was established, reversed the decrease in EPSC, but not in IPSC, amplitude. Direct activation of the CB(1) receptor by WIN 55,212-2 initiated synaptic depression that was independent of afferent stimulation. These findings indicate that retrograde eCB signaling requires a postsynaptic release step involving a transporter or carrier that is activated by afferent stimulation/synaptic activation.

Long-term synaptic plasticity in the spinal dorsal horn and its modulation by electroacupuncture in rats with neuropathic pain

Our previous study has reported that electroacupuncture (EA) at low frequency of 2 Hz had greater and more prolonged analgesic effects on mechanical allodynia and thermal hyperalgesia than that EA at high frequency of 100 Hz in rats with neuropathic pain. However, how EA at different frequencies produces distinct analgesic effects on neuropathic pain is unclear. Neuronal plastic changes in spinal cord might contribute to the development and maintenance of neuropathic pain. In the present study, we investigated changes of spinal synaptic plasticity in the development of neuropathic pain and its modulation by EA in rats with neuropathic pain. Field potentials of spinal dorsal horn neurons were recorded extracellularly in sham-operated rats and in rats with spinal nerve ligation (SNL). We found for the first time that the threshold for inducing long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn was significantly lower in SNL rats than that in sham-operated rats. The threshold for evoking the C-fiber-evoked field potentials was also significantly lower, and the amplitude of the field potentials was higher in SNL rats as compared with those in the control rats. EA at low frequency of 2 Hz applied on acupoints ST 36 and SP 6, which was effective in treatment of neuropathic pain, induced long-term depression (LTD) of the C-fiber-evoked potentials in SNL rats. This effect could be blocked by N-methyl- d-aspartic acid (NMDA) receptor antagonist MK-801 and by opioid receptor antagonist naloxone. In contrast, EA at high frequency of 100 Hz, which was not effective in treatment of neuropathic pain, induced LTP in SNL rats but LTD in sham-operated rats. Unlike the 2 Hz EA-induced LTD in SNL rats, the 100 Hz EA-induced LTD in sham-operated rats was dependent on the endogenous GABAergic and serotonergic inhibitory system. Results from our present study suggest that (1) hyperexcitability in the spinal nociceptive synaptic transmission may occur after nerve injury, which may contribute to the development of neuropathic pain; (2) EA at low or high frequency has a different effect on modulating spinal synaptic plasticities in rats with neuropathic pain. The different modulation on spinal LTD or LTP by low- or high-frequency EA may be a potential mechanism of different analgesic effects of EA on neuropathic pain. LTD of synaptic strength in the spinal dorsal horn in SNL rats may contribute to the long-lasting analgesic effects of EA at 2 Hz.

NMDA Receptor-dependent Long-term Depression in the Anterior Cingulate Cortex

Neurons and synapses in the mammalian brain exhibit plastic changes, which occur not only during development and under physiological conditions, but also under pathological conditions. One major cellular hypothesis is that activity-dependent changes in synaptic strength may contribute to the formation of memory and the expression of persistent inflammatory pain. Recently, the anterior cingulate cortex (ACC) has been proposed to play an important role for learning, memory and chronic pain. Long-term potentiation (LTP) and long-term depression (LTD) are well-studied phenomena which may be related to learning and memory. NMDA receptors are the most important trigger for LTP and LTD of synaptic strength. Here, we review recent studies and present new experimental data on the roles of NMDA receptors during synaptic depression in the ACC. Furthermore, we consider the physiological and pathological significance of LTD in the ACC.

A paired-pulse facilitation analysis of long-term synaptic depression at excitatory synapses in rat hippocampal CA1 and CA3 regions

Paired-pulse facilitation (PPF) is a form of short-term, activity-dependent synaptic plasticity common to most chemically transmitting synapses, manifested as an enhancement in the amplitude of the second of two rapidly evoked excitatory postsynaptic potentials (EPSPs). The generally accepted explanation of PPF posits that residual intraterminal free [Ca 2+] from the first action potential facilitates the probability of transmitter release evoked by the second stimulus. A common extension of this hypothesis postulates that any plastic change which alters the probability of transmitter release, should also alter the magnitude of PPF. In the present study, we examined the relationship between PPF and both stimulus- and chemically-evoked long-term depression of synaptic strength (LTD) at Schaffer collateral-CA1, commissural/associational-CA3 and mossy fiber-CA3 synapses in rat hippocampal slices. We observed no significant change in mean PPF associated with either electrically- or chemically-induced LTD at any of these synapses. However, a correlation analysis revealed a complex pattern of PPF changes with LTD, such that low initial PPF was correlated with increases in PPF, while high initial PPF was associated with decreases. Combined with previous findings supporting a presynaptic site for chemical and stimulus-evoked LTD, our current data suggests a complex set of neurosecretory modifications downstream of presynaptic Ca 2+ influx, may, at least in part, underlie the expression of LTD.

Activation of group I metabotropic glutamate receptors induces long-term depression at sensory synapses in superficial spinal dorsal horn

Low-frequency stimulation of primary afferent A δ-fibers can induce long-term depression of synaptic transmission in rat superficial spinal dorsal horn. Here, we have identified another form of long-term depression in superficial spinal dorsal horn neurons that is induced by specific group I but not group II metabotropic glutamate receptor (mGluR) agonists. Synaptic strength between A δ-fibers and dorsal horn neurons was examined by intracellular recordings in a spinal cord–dorsal root slice preparation from young rat. In the presence of bicuculline and strychnine, bath application of (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1 S,3 R)-ACPD) or the specific group I mGluR agonist ( S)-3,5-dihydroxyphenylglycine (( S)-3,5-DHPG) but not the specific group II mGluR agonist (2 S,2′ R,3′ R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) for 20 min produced an acute and a long-term depression of synaptic strength. Bath application of the N-methyl- d-aspartate receptor antagonist d-2-amino-5-phosphonovaleric acid did not affect these depressions by (1 S,3 R)-ACPD. After pre-incubation of slices with pertussis toxin, a G-protein inhibitor, (1 S,3 R)-ACPD still induced acute and long-term depressions. The phospholipase C inhibitor U73122 stereoselectively blocked the induction of long-term depression without affecting acute synaptic inhibition. This study demonstrates that, in the spinal cord, direct activation of group I mGluRs that are coupled to phospholipase C through pertussis toxin-insensitive G-proteins induces a long-term depression of synaptic strength. This may be relevant to the processing of sensory information in the spinal cord, including nociception.

Reciprocal interactions between CA3 network activity and strength of recurrent collateral synapses.

In hippocampal slices, synchronous CA3 network activity induced persistent strengthening of active positive-feedback synapses. This altered network operation by increasing probability of future synchronous network activation. Long-term depression of synaptic strength induced by partial blockade of NMDA receptors during synchronous network activity reversed changes in probability of spontaneous network activation. These results suggest that specific network activity patterns selectively alter strength of active synapses. Stable, reversible alterations in network activity can also be effected by corresponding alterations in synaptic strength. These findings confirm the Hebb memory model at the neural-network level and suggest new therapies for pathological patterns of network activity in epilepsy.

CXC chemokines interleukin-8 (IL-8) and growth-related gene product α (GROα) modulate Purkinje neuron activity in mouse cerebellum

We give here evidence that Purkinje neurons (PNs) of mouse cerebellar slices studied with patch clamp technique combined with laser confocal microscopy, respond to human IL-8 and GROα by (i) a cytosolic Ca 2+ transient compatible with inositol (1,4,5) trisphosphate (InsP 3) formation; (ii) an enhancement of the neurotransmitter release; and (iii) an impairment of the long-term depression of synaptic strength (LTD). It was also found the expression of IL-8 receptor type 2 in PN and granule cells by immunofluorescence, immunoblotting and RT-PCR analysis. Considered together these findings suggest that IL-8 and GROα may play a neuromodulatory role on mouse cerebellum.

Transient and persistent increases in protein phosphatase activity during long-term depression in the adult hippocampus in vivo

The neural substrates of learning and memory most likely involve activity-dependent long-term changes in synaptic strength, including long-term potentiation and long-term depression. [3, 18]A critical element in the cascade of events hypothesized to underlie such changes in synaptic function is modification of protein phosphorylation. [17, 28, 29]Long-term depression is thought to involve decreases in protein phosphorylation, which could result from reduction in protein kinase activity [12]and/or enhancement in protein phosphatase activity. [22, 23]We present here direct evidence that long-term depression in the hippocampus in vivo is associated with an increase in the activity of the serine/threonine phosphatases 1 and 2A. The increase in activity of phosphatase 1 was transient, whereas that of phosphatase 2A lasted >65 min after the induction of long-term depression. Blockade of long-term depression prevented the observed increases in phosphatase activity, as did selective inhibition of phosphatase 1 and 2A. Induction of long-term depression had no effect on the level of either phosphatase, which suggests that our results reflect increases in the intrinsic activity of these two enzymes. Our findings are consistent with a model of synaptic plasticity [16–18, 22, 23]that implicates protein dephosphorylation by serine/threonine phosphatases in the early maintenance and/or expression of long-term depression of synaptic strength.

Long-term plasticity in cingulate cortex requires both NMDA and metabotropic glutamate receptor activation

We tested whether induction of homosynaptic long-term potentiation and long-term depression of synaptic strength in posterior cingulate cortex requires NMDA and/or metabotropic glutamate (mGlu) receptor activation. In in-vitro slices of rat posterior cingulate cortex, the NMDA receptor antagonist d-2-amino-5-phosphonopentanoic acid ( d-AP5; 15–20 μM) blocked induction of both long-term potentiation and long-term depression of mono- and polysynaptic population potentials in deep laminae. In contrast, dl-2-amino-3-phosphonopropionic acid ( dl-AP3; 15–25 μM), a selective mGlu receptor antagonist, blocked homosynaptic long-term potentiation and long-term depression of monosynaptic transmission, but was ineffective in blocking the induction of either type of plasticity at polysynaptically-driven sites. The selective mGlu receptor agonist, trans-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), induced a marked depression of subicular-evoked monosynaptic potentials which reversed upon drug washout, but produced little depression of polysynaptic responses. We conclude that metabotropic glutamate receptor activation is necessary for the induction of long-term synaptic plasticity only at monosynaptic subiculo-cingulate terminals, while NMDA receptor activation is necessary for the induction of long-term potentiation/long-term depression of both mono- and polysynaptic pathways.

Phospholipase A 2 activation is not required for long-term synaptic depression

Low-frequency synaptic stimulation evokes long-term depression of synaptic strength. One hypothesis is that modification of AMPA receptors by phospholipase A 2 causes long-term depression. A previous study reported bromophenacylbromide, a completely nonselective phospholipase A 2 inhibitor, blocked long-term depression at Schaffer collateral-CA1 synapses in hippocampus. In contrast, I show here that 3-(4-octadecyl)-benzoylacrylic acid (OBAA), a much more potent and selective inhibitor of low and high molecular weight phospholipase A 2, does not block long-term depression at these same synapses, indicating that phospholipase A 2 is not necessary for modifications causing long-term depression.

Associative long-term depression in the hippocampus induced by hebbian covariance

A brief, high-frequency activation of excitatory synapses in the hippocampus produces a long-lasting increase in synaptic strengths called long-term potentiation (LTP). A test input, which by itself does not have a long-lasting effect on synaptic strengths, can be potentiated through association when it is activated at the same time as a separate conditioning input. Neural network modelling studies have also predicted that synaptic strengths should be weakened when test and conditioning inputs are anti-correlated. Evidence for such heterosynaptic depression in the hippocampus has been found for inputs that are inactive or weakly active during the stimulation of a conditioning input, but this depression does not depend on any pattern of test input activity and does not seem to last as long as LTP. We report here an associative long-term depression (LTD) in field CA1 that is produced when a low-frequency test input is negatively correlated in time with a high-frequency conditioning input. LTD of synaptic strength is also produced by activating presynaptic terminals while a postsynaptic neuron is hyperpolarized. This confirms theoretical predictions that the mechanism for associative LTD is homosynaptic and follows a hebbian covariance rule.