LTP) And Depression Induction Research Articles

Bidirectional and long-lasting control of alcohol-seeking behavior by corticostriatal LTP and LTD.

Addiction is proposed to arise from alterations in synaptic strength via mechanisms of long-term potentiation (LTP) and depression (LTD). However, the causality between these synaptic processes and addictive behaviors is difficult to demonstrate. Here we report that LTP/LTD induction altered operant alcohol self-administration, a motivated drug-seeking behavior. We first induced LTP by pairing presynaptic glutamatergic stimulation with optogenetic postsynaptic depolarization in the dorsomedial striatum, a brain region known to control goal-directed behavior. Blockade of this LTP by NMDA receptor inhibition unmasked an endocannabinoid-dependent LTD. In vivo application of the LTP-inducing protocol caused a long-lasting increase in alcohol-seeking behavior, while the LTD protocol decreased this behavior. We further identified that optogenetic LTP/LTD induction at cortical inputs onto striatal dopamine D1 receptor-expressing neurons controlled these behavioral changes. Our results demonstrate a causal link between synaptic plasticity and alcohol-seeking behavior, and that modulation of this plasticity may inspire a therapeutic strategy for addiction.

Distinct Roles of Protein Phosphatase 1 Bound on Neurabin and Spinophilin and Its Regulation in AMPA Receptor Trafficking and LTD Induction.

Protein phosphatase-1 (PP1) constrains learning and memory formation in part through its effects on the induction threshold of long-term potentiation (LTP) and depression (LTD). LTD induction requires both the enzymatic activity of PP1 and its proper anchoring to synaptic spines. We have shown previously that neurabin, a major synaptic scaffolding protein, targets PP1 to synapses for LTD induction. Here, we show that PP1 bound on spinophilin, a close homolog of neurabin and another major synaptic PP1 anchoring protein, does not play a role in LTD induction, which suggests that neurabin plays a privileged role in nanodomain targeting of PP1 in LTD induction. We found that protein kinase A can significantly weaken the neurabin-PP1 interaction in neurons via phosphorylation of neurabin at serine 461, a phosphorylation site adjacent to the PP1-binding motif that is not conserved in spinophilin. Finally, we found that a neurabin mutation (S461E), which mimics phosphorylation, blocked AMPA receptor endocytosis and LTD induction. The results indicate the critical importance of nanodomain targeting of PP1 within synaptic spines and its regulation in LTD induction.

Induction of long-term potentiation and depression in individual synapses of CA1 pyramidal neurons

Long-Term Potentiation (LTP) and Depression (LTD), the two major forms of long-lasting synaptic plasticity in the mammalian neurons, represent a basic step to understand neuronal development, circuit reorganization, learning and memory mechanisms. Experimental studies on LTP and LTD are usually performed using in vitro or in vivo preparations, exploiting repetitive and properly patterned stimulation protocols to induce long-lasting changes in the strength of a synaptic connection. Although the underlying molecular mechanisms are starting to be unraveled and are under intense experimental and theoretical scrutiny, especially in the CA1 region of the hippocampus, experimenters often report problems in using standard induction protocols to obtain consistent results, especially for LTD in vivo. We hypothesize that a possible source of confusion in interpreting the results, from any given experiment on synaptic plasticity, can be the intrinsic limitation of the experimental techniques, which cannot take into account the actual state and peak conductance of the synapses before the conditioning protocol. Within this context, using biophysical models of synaptic plasticity and hippocampal CA1 pyramidal neurons, we investigate the relation between what is observed at the soma and LTP/LTD induction patterns, pre-conditioning synaptic strength, and dendritic location. Our model and the results pointed out that the outcome of an experiment, testing the amount of synaptic LTP/LTD plasticity that can be induced, strongly depends at least on the initial synaptic state and peak conductance. In addition, the model explains why LTD induction may be more critical to be obtained, with respect to LTP, especially in vivo, and suggests experimentally testable predictions on the stimulation protocols that may be more effective.

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.

Activity-Dependent Transcription of BDNF Enhances Visual Acuity during Development

In the developing Xenopus tadpole, conditioning with 20 min of visual stimulation leads to increased proBDNF protein levels in the tectum measured 4 hr later. Following conditioning, the ability to induce direction selectivity in tectal neurons, as well as both retinotectal long-term potentiation and depression, thought to underlie this phenomenon, was strongly facilitated. This facilitation was blocked by knockdown of BDNF expression in tectal neurons. Animals that had been exposed to visual conditioning and subsequently received normal visual input for 7-11 hr exhibited higher spatial frequency thresholds of tectal cell responses to counterphasing gratings than nonconditioned control animals. An improvement in visual acuity was confirmed by enhanced sensitivity to counterphasing gratings in a behavioral test. These results indicate that brief sensory stimulation, by initiating nuclear transcription and de novo protein synthesis of BDNF, can facilitate the refinement of response properties in the developing visual system.

Age-Dependent Decline in Supragranular Long-Term Synaptic Plasticity by Increased Inhibition During the Critical Period in the Rat Primary Visual Cortex

Supragranular long-term potentiation (LTP) and depression (LTD) are continuously induced in the pathway from layer 4 during the critical period in the rodent primary visual cortex, which limits the use of supragranular long-term synaptic plasticity as a synaptic model for the mechanism of ocular dominance (OD) plasticity. The results of the present study demonstrate that the pulse duration of extracellular stimulation to evoke a field potential (FP) is critical to induction of LTP and LTD in this pathway. LTP and LTD were induced in the pathway from layer 4 to layer 2/3 in slices from 3-wk-old rats when FPs were evoked by 0.1- and 0.2-ms pulses. LTP and LTD were induced in slices from 5-wk-old rats when evoked by stimulation with a 0.2-ms pulse but not by stimulation with a 0.1-ms pulse. Both the inhibitory component of FP and the inhibitory/excitatory postsynaptic potential amplitude ratio evoked by stimulation with a 0.1-ms pulse were greater than the values elicited by a 0.2-ms pulse. Stimulation with a 0.1-ms pulse at various intensities that showed the similar inhibitory FP component with the 0.2-ms pulse induced both LTD and LTP in 5-wk-old rats. Thus extracellular stimulation with shorter-duration pulses at higher intensity resulted in greater inhibition than that observed with longer-duration pulses at low intensity. This increased inhibition might be involved in the age-dependent decline of synaptic plasticity during the critical period. These results provide an alternative synaptic model for the mechanism of OD plasticity.

Inhibiting dopamine reuptake blocks the induction of long-term potentiation and depression in the lateral entorhinal cortex of awake rats

Synaptic plasticity in olfactory inputs to the lateral entorhinal cortex may result in lasting changes in the processing of olfactory stimuli. Changes in dopaminergic tone can have strong effects on basal evoked synaptic responses in the superficial layers of the entorhinal cortex, and the current study investigated whether dopamine may modulate the induction of long-term potentiation (LTP) and depression (LTD) in piriform cortex inputs to layer II of the lateral entorhinal cortex in awake rats. Groups of animals were pretreated with either saline or the selective dopamine reuptake inhibitor GBR12909 prior to low or high frequency stimulation to induce LTD or LTP. In saline-treated groups, synaptic responses were potentiated to 122.4+/-6.4% of baseline levels following LTP induction, and were reduced to 84.5+/-4.9% following induction of LTD. Changes in synaptic responses were maintained for up to 60min and returned to baseline levels within 24h. In contrast, induction of both LTP and LTD was blocked in rats pretreated with GBR12909. Dopaminergic suppression of synaptic plasticity in the entorhinal cortex may serve to restrain activity-dependent plasticity during reward-relevant behavioral states or during processing of novel stimuli.

Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD

Protein synthesis-dependent, synapse input-specific late phases of long-term potentiation (LTP) and depression (LTD) may underlie memory formation at the cellular level. Recently, it was described that the induction of LTP can mark a specifically activated synapse by a synaptic tag to capture synapse non-specific plasticity-related proteins (PRPs) and thus maintaining input-specific LTP for prolonged periods. Here we show in rat hippocampal slices in vitro, that the induction of protein synthesis-dependent late-LTD is also characterized by synaptic tagging and that heterosynaptic induction of either LTD or LTP on two sets of independent synaptic inputs S1 and S2 can lead to late-associative interactions: early-LTD in S2 was transformed into a late-LTD, if late-LTP was induced in S1. The synthesis of process-independent PRPs by late-LTP in S1 was sufficient to transform early- into late-LTD in S2 when process-specific synaptic tags were set. We name this new associative property of cellular information processing ‘cross-tagging.’

Compatibility of bidirectional synaptic plasticity on hippocampo-prefrontal cortex pathway in rats

The hippocampo-prefrontal cortex pathway reportedly expresses long-term potentiation (LTP) and depression (LTD) in anesthetized rats. We examined whether there were any effects governing the induction of LTD after prior induction of LTP, or vice versa. Induction in sequence of LTP and LTD resulted in significantly stable changes of about 140 and 70% of a common control for 1 h each. The reversed sequence, LTD and LTP, showed a mirror image of about 65 and 135% of control, which were not different from the respective changes in the first sequence ( P>0.3 for each). The correlation coefficient between changes was significantly positive in the first sequence and weakly negative in the reverse. These results indicate that this pathway can express compatibility of bidirectional synaptic plasticity while historical changes remain covert.

Long-term synaptic plasticity between pairs of individual CA3 pyramidal cells in rat hippocampal slice cultures.

1. Long-term potentiation (LTP) and depression (LTD) were investigated at synapses formed by pairs of monosynaptically connected CA3 pyramidal cells in rat hippocampal slice cultures. 2. An N-methyl-D-aspartate (NMDA) receptor-mediated component of the unitary EPSP, elicited at the resting membrane potential in response to single action potentials in an individual CA3 cell, could be isolated pharmacologically. 3. Associative LTP was induced when single presynaptic action potentials were repeatedly paired with 240 ms postsynaptic depolarizing pulses that evoked five to twelve action potentials or with single postsynaptic action potentials evoked near the peak of the unitary EPSP. LTP induction was prevented by an NMDA receptor antagonist. 4. Associative LTD was induced when single presynaptic action potentials were repeatedly elicited with a certain delay after either 240 ms postsynaptic depolarizing pulses or single postsynaptic action potentials. The time window within which presynaptic activity had to occur for LTD induction was dependent on the amount of postsynaptic depolarization. LTD was induced if single pre- and postsynaptic action potentials occurred synchronously. 5. Homosynaptic LTD was induced by 3 Hz tetanization of the presynaptic neuron for 3 min and was blocked by an NMDA receptor antagonist. 6. Depotentiation was produced with stimulation protocols that elicit either homosynaptic or associative LTD. 7. Recurrent excitatory synapses between CA3 cells display associative potentiation and depression. The sign of the change in synaptic strength is a function of the relative timing of pre- and postsynaptic action potentials.

Possible roles of retrograde messengers on LTP, LTD, and associative memory

There are still no clear biophysical models for Associative Long-Term Potentiation (LTP) and Depression (LTD) in the hippocampus, where two populations of synapses targeted to the same receptive field are involved. Here we propose a model that allows an interpretation of the experiments in terms of the molecular processes that may be involved in associative memory. The model suggests that retrograde messengers could have a critical role in the induction and maintenance of associative LTP and LTD, by controlling the coupling between the two populations of synapses.