Amplitude Of Long-term Depression Research Articles

A Novel CaMKII Inhibitory Peptide Blocks Relapse to Morphine Seeking by Influencing Synaptic Plasticity in the Nucleus Accumbens Shell.

Drugs of abuse cause enduring functional disorders in the brain reward circuits, leading to cravings and compulsive behavior. Although people may rehabilitate by detoxification, there is a high risk of relapse. Therefore, it is crucial to illuminate the mechanisms of relapse and explore the therapeutic strategies for prevention. In this research, by using an animal model of morphine self-administration in rats and a whole-cell patch–clamp in brain slices, we found changes in synaptic plasticity in the nucleus accumbens (NAc) shell were involved in the relapse to morphine-seeking behavior. Compared to the controls, the amplitude of long-term depression (LTD) induced in the medium spiny neurons increased after morphine self-administration was established, recovered after the behavior was extinguished, and increased again during the relapse induced by morphine priming. Intravenous injection of MA, a new peptide obtained by modifying Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor “myr-AIP”, decreased CaMKII activity in the NAc shell and blocked the reinstatement of morphine-seeking behavior without influence on the locomotor activity. Moreover, LTD was absent in the NAc shell of the MA-pretreated rats, whereas it was robust in the saline controls in which morphine-seeking behavior was reinstated. These results indicate that CaMKII regulates morphine-seeking behavior through its involvement in the change of synaptic plasticity in the NAc shell during the relapse, and MA may be of great value in the clinical treatment of relapse to opioid seeking.

Impact of blunting astrocyte activity on hippocampal synaptic plasticity in a mouse model of early Alzheimer's disease based on amyloid-β peptide exposure.

Amyloid-β peptides (Aβ) accumulate in the brain since early Alzheimer's disease (AD) and dysregulate hippocampal synaptic plasticity, the neurophysiological basis of memory. Although the relationship between long-term potentiation (LTP) and memory processes is well established, there is also evidence that long-term depression (LTD) may be crucial for learning and memory. Alterations in synaptic plasticity, namely in LTP, can be due to communication failures between astrocytes and neurons; however, little is known about astrocytes' ability to control hippocampal LTD, particularly in AD-like conditions. We now aimed to test the involvement of astrocytes in changes of hippocampal LTP and LTD triggered by Aβ1-42 , taking advantage of L-α-aminoadipate (L-AA), a gliotoxin that blunts astrocytic function. The effects of Aβ1-42 exposure were tested in two different experimental paradigms: ex vivo (hippocampal slices superfusion) and in vivo (intracerebroventricular injection), which were previously validated to impair memory and hippocampal synaptic plasticity, two features of early AD. Blunting astrocytic function with L-AA reduced LTP and LTD amplitude in hippocampal slices from control mice, but the effect on LTD was less evident, suggesting that astrocytes have a greater influence on LTP than on LTD under non-pathological conditions. However, under AD conditions, blunting astrocytes did not consistently alter the reduction of LTP magnitude, but reverted the LTD-to-LTP shift caused by both ex vivo and in vivo Aβ1-42 exposure. This shows that astrocytes were responsible for the hippocampal LTD-to-LTP shift observed in early AD conditions, reinforcing the interest of strategies targeting astrocytes to restore memory and synaptic plasticity deficits present in early AD.

A Model of Induction of Cerebellar Long-Term Depression Including RKIP Inactivation of Raf and MEK.

We report an updated stochastic model of cerebellar Long Term Depression (LTD) with improved realism. Firstly, we verify experimentally that dissociation of Raf kinase inhibitor protein (RKIP) from Mitogen-activated protein kinase kinase (MEK) is required for cerebellar LTD and add this interaction to an earlier published model, along with the known requirement of dissociation of RKIP from Raf kinase. We update Ca2+ dynamics as a constant-rate influx, which captures experimental input profiles accurately. We improve α-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor interactions by adding phosphorylation and dephosphorylation of AMPA receptors when bound to glutamate receptor interacting protein (GRIP). The updated model is tuned to reproduce experimental Ca2+ peak vs. LTD amplitude curves at four different Ca2+ pulse durations as closely as possible. We find that the updated model is generally more robust with these changes, yet we still observe some sensitivity of LTD induction to copy number of the key signaling molecule Protein kinase C (PKC). We predict natural variability in this number by stochastic diffusion may influence the probabilistic LTD response to Ca2+ input in Purkinje cell spines and propose this as an extra source of stochasticity that may be important also in other signaling systems.

Depression biased non-Hebbian spike-timing-dependent synaptic plasticity in the rat subiculum.

The subiculum is a structure that forms a bridge between the hippocampus and the entorhinal cortex (EC), and plays a major role in the memory consolidation process. Here, we demonstrate spike-timing-dependent plasticity (STDP) at the proximal excitatory inputs on the subicular pyramidal neurons of juvenile rat. Causal (positive) pairing of a single EPSP with a single back-propagating action potential (bAP) after a time interval of 10ms (+10ms) failed to induce plasticity. However, increasing the number of bAPs in a burst to three, at two different frequencies of 50Hz (bAP burst) and 150Hz, induced long-term depression (LTD) after a time interval of +10ms in both the regular-firing (RF), and the weak burst firing (WBF) neurons. The LTD amplitude decreased with increasing time interval between the EPSP and the bAP burst. Reversing the order of the pairing of the EPSP and the bAP burst induced LTP at a time interval of -10ms. This finding is in contrast with reports at other synapses, wherein pre- before postsynaptic (causal) pairing induced LTP and vice versa. Our results reaffirm the earlier observations that the relative timing of the pre- and postsynaptic activities can lead to multiple types of plasticity profiles. The induction of timing-dependent LTD (t-LTD) was dependent on postsynaptic calcium change via NMDA receptors in the WBF neurons, while it was independent of postsynaptic calcium change, but required active L-type calcium channels in the RF neurons. Thus the mechanism of synaptic plasticity may vary within a hippocampal subfield depending on the postsynaptic neuron involved. This study also reports a novel mechanism of LTD induction, where L-type calcium channels are involved in a presynaptically induced synaptic plasticity. The findings may have strong implications in the memory consolidation process owing to the central role of the subiculum and LTD in this process.

Induction of cerebellar long-term depression requires activation of calcineurin in Purkinje cells

Cerebellar long-term depression (LTD) is an activity-dependent depression of synaptic transmission from parallel fibers to Purkinje cells underlying certain forms of motor learning. LTD is induced by the conjunctive stimulation of parallel fibers and climbing fibers, both of which supply excitatory inputs to Purkinje cells. The conjunctive stimulation induces a large increase in intracellular Ca 2+ concentration ([Ca 2+] i) in Purkinje cells. Although the increase in [Ca 2+] i is essential for LTD induction, the downstream signal transduction mechanism remains elusive. In this study, we show that LTD induction requires the activation of the Ca 2+/calmodulin-dependent protein phosphatase 2B calcineurin. In acute cerebellar slices of mice, the LTD amplitude was significantly reduced in the presence of calcineurin inhibitors (cyclosporin A or FK506), whereas the basic electrophysiological properties of the parallel fiber-Purkinje cell synaptic transmission remained constant. Furthermore, a calcineurin autoinhibitory peptide perfused into Purkinje cells completely blocked LTD induction. On the other hand, microcystin LR, an inhibitor of protein phosphatase 1 and 2A, did not affect the induction of LTD. These results indicate that calcineurin activation is essential for LTD induction downstream of the conjunctive-stimulation-induced Ca 2+ signal in Purkinje cells.

Early chronic aluminium exposure impairs long-term potentiation and depression to the rat dentate gyrus in vivo

As an important neurotoxin, aluminium can cause cognitive dysfunctions and mental diseases. Previous studies have reported that aluminium impaired long-term potentiation (LTP) in vivo and in vitro. Here, we utilise two models of synaptic plasticity, LTP and long-term depression (LTD) to study the effects of aluminium on synaptic plasticity in vivo. Neonatal Wistar rats were chronically exposed to aluminium from birth to weaning via the milk of dams fed with 0.3% aluminium chloride solution. Excitatory postsynaptic potential (EPSP) and population spikes (PS) were recorded from the dentate gyrus (DG) of adult rats by electrically stimulating the perforant path. The following results were obtained: (1) The input/output function indicated that, as compared to controls, aluminium increased the baseline amplitude of the PS, but decreased the baseline slope of EPSP. (2) Aluminium significantly prevented LTD in PS (controls: 77.36±6.7%, n=7; aluminium-exposed: 102.01±9.1%, n=7; P<0.05) and decreased the LTD amplitude in EPSP (controls: 76.61±4.1%, n=7; aluminium-exposed: 94.31±7.9% n=7, P<0.05). (3) Aluminium reduced the amplitude of LTP in both PS (controls: 190±16.1%, n=7; aluminium-exposed: 135±9.7%, n=7; P<0.05) and EPSP (control: 132±9.3%, n=7; aluminium-exposed: 115±10.6%, n=7; P<0.05). As for LTD and LTP, PS was impaired more seriously than EPSP in aluminium-exposed rats. (4) Aluminium exposure decreased the paired-pulse facilitation (PPF) of PS at 30–150 ms interpulse interval (IPI), and reduced 93.5% of PPF at 80 ms IPI in PS (controls: 243.4±39.8%, n=7; aluminium-exposed: 149.9±12.3%, n=7). There was no significant difference in EPSP of PPF. From these results we conclude that aluminium exposure in neonatal rats thus reduces the amplitude of LTP and PPF and blocks the induction of LTD in the DG. We suggest that aluminium affects both presynaptic and postsynaptic mechanisms of synaptic transmission.

Ifenprodil and ethanol enhance NMDA receptor-dependent long-term depression.

Long-term alterations in synaptic transmission are thought to underlie various types of alcohol-related brain disorders. While ethanol effects on synaptic potentiation are well documented, ethanol effects on synaptic depression have not been addressed. Herein, we performed experiments to assess the role of ethanol on long-term depression (LTD) formation. In rat hippocampal slices, prolonged low-frequency stimulation (LFS) of CA1 Schaffer collaterals (1 Hz for 7 min) induced saturable, long-lasting, reversible N-methyl-D-aspartate (NMDA) receptor-dependent LTD of stimulus-evoked dendritic population excitatory postsynaptic potentials. This depression (-26% LTD amplitude) was observed in young rats (12-20 days old), but not adult rats (28-35 days old). Induction of LTD was blocked (-3% LTD amplitude) when the LFS was delivered in the presence of the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid. When the conditioning LFS was delivered in the presence of ethanol, there was a significant enhancement in the induction of NMDA receptor-dependent LTD versus control LTD (-36% LTD amplitude). Ifenprodil, an N-methyl-D-aspartate receptor subunit 2B (NR2B)-selective antagonist, also significantly facilitated the induction of LTD (-40% LTD amplitude). Consistent with this result, ifenprodil did not affect the NMDA receptor-dependent component of the baseline synaptic response, whereas D-2-amino-5-phosphonovaleric acid caused significant depression of the NMDA component. These data indicate that whereas ethanol is known to inhibit NMDA receptor function in a variety of systems, it significantly enhances the induction of NMDA receptor-dependent LTD. Furthermore, since ifenprodil is known to select for ethanol-sensitive subtypes of NR2B-NMDA receptors, these data also suggest that NR2B-containing NMDA receptor subpopulations do not contribute to LTD, but instead may actually play inhibitory roles in LTD induction.

Selective involvement of mGlu1 receptors in corticostriatal LTD

Although metabotropic glutamate receptors (mGluRs) have been proposed to play a role in corticostriatal long-term depression (LTD), the specific receptor subtype required for this form of synaptic plasticity has not been characterized yet. Thus, we utilized a corticostriatal brain slice preparation and intracellular recordings from striatal spiny neurons to address this issue. We observed that both AIDA (100 μM) and LY 367385 (30 μM), two blockers of mGluR1s, were able to fully prevent the induction of this form of synaptic plasticity, whereas MPEP (30 μM), a selective antagonist of the mGluR5 subtype, did not significantly affect the amplitude and time-course of corticostriatal LTD. Both AIDA and LY 367385 were ineffective on LTD when applied after its induction. The critical role of mGluR1s in the formation of corticostriatal LTD was confirmed in experiments performed on mice lacking mGluR1s. In these mice, in fact, a significant reduction of the LTD amplitude was observed in comparison to the normal LTD measured in their wild-type counterparts. We found that neither acute pharmacological blockade of mGluR1s nor the genetic disruption of these receptors affected the presynaptic modulation of corticostriatal excitatory postsynapic potentials (EPSPs) exerted by DCG-IV and L-SOP, selective agonists of group II and III mGluRs, respectively. Our data show that the induction of corticostriatal LTD requires the activation of mGluR1 but not mGluR5. mGluR1-mediated control of this form of synaptic plasticity may play a role in the modulatory effect exerted by mGluRs in the basal ganglia-related motor activity.