MGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning.
ABSTRACT: Highly selective positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have emerged as a potential approach to treat positive symptoms associated with schizophrenia. mGluR5 plays an important role in both long-term potentiation (LTP) and long-term depression (LTD), suggesting that mGluR5 PAMs may also have utility in improving impaired cognitive function. However, if mGluR5 PAMs shift the balance of LTP and LTD or induce a state in which afferent activity induces lasting changes in synaptic function that are not appropriate for a given pattern of activity, this could disrupt rather than enhance cognitive function. We determined the effect of selective mGluR5 PAMs on the induction of LTP and LTD at the Schaffer collateral-CA1 synapse in the hippocampus. mGluR5-selective PAMs significantly enhanced threshold theta-burst stimulation (TBS)-induced LTP. In addition, mGluR5 PAMs enhanced both DHPG-induced LTD and LTD induced by the delivery of paired-pulse low-frequency stimulation. Selective potentiation of mGluR5 had no effect on LTP induced by suprathreshold TBS or saturated LTP. The finding that potentiation of mGluR5-mediated responses to stimulation of glutamatergic afferents enhances both LTP and LTD and supports the hypothesis that the activation of mGluR5 by endogenous glutamate contributes to both forms of plasticity. Furthermore, two systemically active mGluR5 PAMs enhanced performance in the Morris water maze, a measure of hippocampus-dependent spatial learning. Discovery of small molecules that enhance both LTP and LTD in an activity-appropriate manner shows a unique action on synaptic plasticity that may provide a novel approach for the treatment of impaired cognitive function.
Project description:Synaptic plasticity of NMDA receptor (NMDAR)-mediated transmission was investigated in the rat dentate gyrus in vitro. Isolated NMDAR EPSCs were recorded from granule cells of the dentate gyrus in response to stimulation of the medial perforant path. Long-term potentiation (LTP) or long-term depression (LTD) of NMDAR EPSCs was observed in response to brief high-frequency stimulation (HFS), with the direction and extent of plasticity dependent on the concentration and type (EGTA vs BAPTA) of the intracellular Ca2+ buffer. LTD was induced in higher concentrations of EGTA and BAPTA than LTP, and BAPTA was approximately 100-fold more potent than EGTA. Although LTD was induced in a high concentration of EGTA (10 mM), a high concentration of BAPTA (10 mM) blocked both LTP and LTD. LTP of AMPA receptor (AMPAR)-EPSCs exhibited a lower dependency on Ca2+ buffering than LTP of NMDAR EPSCs, because LTP of AMPAR EPSCs was induced by HFS in high EGTA (10 mM). We also identified a role for metabotropic glutamate receptor 5 (mGluR5) in NMDAR plasticity. HFS LTD was blocked by the group I/II mGluR antagonist LY341495 ((2S)-2-amino-2-[(1S, 2S)-2-carboxycycloprop-1-yl]-3(xanth-9-yl)propanoic acid) and by the mGluR5-selective antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). Similarly, low-frequency stimulation-induced LTD of NMDAR EPSCs was also blocked by MPEP. These findings suggest that the direction of plasticity of NMDARs is determined by the intracellular free Ca2+ concentration and is dependent on activation of mGluR5.
Project description:In animal models of Alzheimer's disease (AD), mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are impaired. In AD patients, LTP-like cortical plasticity is abolished, whereas LTD seems to be preserved. Dopaminergic transmission has been hypothesized as a new player in ruling mechanisms of cortical plasticity in AD. We aimed at investigating whether administration of the dopamine agonist rotigotine (RTG) could modulate cortical plasticity in AD patients, as measured by theta burst stimulation (TBS) protocols of repetitive transcranial stimulation applied over the primary motor cortex. Thirty mild AD patients were tested in three different groups before and after 4 weeks of treatment with RTG, rivastigmine (RVT), or placebo (PLC). Each patient was evaluated for plasticity induction of LTP/LTD-like effects using respectively intermittent TBS (iTBS) or continuous TBS protocols. Short-latency afferent inhibition (SAI) protocol was performed to indirectly assess central cholinergic activity. A group of age-matched healthy controls was recruited for baseline comparisons. Results showed that at baseline, AD patients were characterized by impaired LTP-like cortical plasticity, as assessed by iTBS. These reduced levels of LTP-like cortical plasticity were increased and normalized after RTG administration. No effect was induced by RVT or PLC on LTP. LTD-like cortical plasticity was not modulated in any condition. Cholinergic activity was increased by both RTG and RVT. Our findings reveal that dopamine agonists may restore the altered mechanisms of LTP-like cortical plasticity in AD patients, thus providing novel implications for therapies based on dopaminergic stimulation.
Project description:Long-term potentiation (LTP) and long-term depression (LTD) are widely accepted to be synaptic mechanisms involved in learning and memory. It remains uncertain, however, which particular activity rules are utilized by hippocampal neurons to induce LTP and LTD in behaving animals. Recent experiments in the dentate gyrus of freely moving rats revealed an unexpected pattern of LTP and LTD from high-frequency perforant path stimulation. While 400 Hz theta-burst stimulation (400-TBS) and 400 Hz delta-burst stimulation (400-DBS) elicited substantial LTP of the tetanized medial path input and, concurrently, LTD of the non-tetanized lateral path input, 100 Hz theta-burst stimulation (100-TBS, a normally efficient LTP protocol for in vitro preparations) produced only weak LTP and concurrent LTD. Here we show in a biophysically realistic compartmental granule cell model that this pattern of results can be accounted for by a voltage-based spike-timing-dependent plasticity (STDP) rule combined with a relatively fast Bienenstock-Cooper-Munro (BCM)-like homeostatic metaplasticity rule, all on a background of ongoing spontaneous activity in the input fibers. Our results suggest that, at least for dentate granule cells, the interplay of STDP-BCM plasticity rules and ongoing pre- and postsynaptic background activity determines not only the degree of input-specific LTP elicited by various plasticity-inducing protocols, but also the degree of associated LTD in neighboring non-tetanized inputs, as generated by the ongoing constitutive activity at these synapses.
Project description:GluN2B subunit containing NMDARs (GluN2B-NMDARs) mediate pathophysiological effects of acutely applied amyloid beta (A?), including impaired long-term potentiation (LTP). However, in transgenic Alzheimer's disease (AD) mouse models which feature gradual A? accumulation, the function of GluN2B-NMDARs and their contribution to synaptic plasticity are unknown. Therefore, we examined the role of GluN2B-NMDARs in synaptic function and plasticity in the hippocampus of PS2APP transgenic mice. Although LTP induced by theta burst stimulation (TBS) was normal in PS2APP mice, it was significantly reduced by the selective GluN2B-NMDAR antagonist Ro25-6981 (Ro25) in PS2APP mice, but not wild type (wt) mice. While NMDARs activated by single synaptic stimuli were not blocked by Ro25, NMDARs recruited during burst stimulation showed larger blockade by Ro25 in PS2APP mice. Thus, the unusual dependence of LTP on GluN2B-NMDARs in PS2APP mice suggests that non-synaptic GluN2B-NMDARs are activated by glutamate that spills out of synaptic cleft during the burst stimulation used to induce LTP. While long-term depression (LTD) was normal in PS2APP mice, and Ro25 had no impact on LTD in wt mice, Ro25 impaired LTD in PS2APP mice, again demonstrating aberrant GluN2B-NMDAR function during plasticity. Together these results demonstrate altered GluN2B-NMDAR function in a model of early AD pathology that has implications for the therapeutic targeting of NMDARs in AD.
Project description:Cognitive comorbidities are increasingly recognized as an equal (or even more disabling) aspect of epilepsy. In addition, the actions of some antiseizure drugs (ASDs) can impact learning and memory. Accordingly, the National Institute of Neurological Disorders and Stroke (NINDS) epilepsy research benchmarks call for the implementation of standardized protocols for screening ASDs for their amelioration or exacerbation of cognitive comorbidities. Long-term potentiation (LTP) is a widely used model for investigating synaptic plasticity and its relationship to learning and memory. Although the effects of some ASDs on LTP have been examined, none of these studies employed physiologically relevant induction stimuli such as theta-burst stimulation (TBS). To systematically evaluate the effects of multiple ASDs in the same preparation using physiologically relevant stimulation protocols, we examined the effects of a broad panel of existing ASDs on TBS-induced LTP in area CA1 of in vitro brain slices, prepared in either normal or sucrose-based artificial cerebrospinal fluid (ACSF), from C57BL/6 mice.Coronal brain slices containing the dorsal hippocampus were made using either standard or sucrose-based ACSF. Recordings were obtained from four slices at a time using the Scientifica Slicemaster high throughput recording system. Slices exposed to ASDs were paired with slices from the opposite hemisphere that served as controls. Field excitatory postsynaptic potentials (fEPSPs) were recorded, and all ASDs were applied to slices by bath perfusion for 20 min prior to the induction stimulus. LTP was induced by TBS or by high-frequency stimulation (HFS). The following ASDs were examined: 100 ?M phenobarbital (PB), 80 ?M phenytoin (PHT), 50 ?M carbamazepine (CBZ), 600 ?M valproate (VPA), 60 ?M topiramate (TPM), 60 ?M lamotrigine (LTG), 100 ?M levetiracetam (LEV), 10 ?M ezogabine (EZG), and 30 ?M tiagabine (TGB).Among voltage-gated sodium channel inhibitors, CBZ significantly attenuated TBS-induced LTP, PHT attenuated both TBS-induced LTP and post-tetanic potentiation (PTP), and LTG failed to affect LTP but did attenuate PTP. ASDs that modulate ?-aminobutyric acid (GABA)ergic synaptic transmission, such as PB and TGB, significantly attenuated LTP in brain slices prepared in sucrose-based ACSF but not standard ACSF. Third generation ASDs, such as LEV and TPM, did not affect LTP in ACSF- or sucrose-prepared brain slices. Although EZG failed to affect LTP, it did significantly attenuate PTP under both slicing conditions. VPA failed to affect LTP in area CA1, both in C57BL/6 mice and Sprague-Dawley rats, using TBS or HFS. However, VPA did attenuate TBS-induced LTP in the dentate gyrus (DG).The results of experiments describe herein provide a comprehensive summary of the effects of many commonly used ASDs on short- and long-term synaptic plasticity while, for the first time, using physiologically relevant LTP induction protocols and slice preparations from mice. Furthermore, methodologic variables, such as brain slice preparation protocols, were explored. These results provide comparative knowledge of ASD effects on synaptic plasticity in the mouse hippocampus and may ultimately contribute to an understanding of the differences in the cognitive side effect profiles of ASDs and the prediction of cognitive dysfunction associated with novel investigational ASDs.
Project description:Theta-burst stimulation (TBS) induces short-term potentiation (STP) plus two types of transcriptionally-independent forms of long-term potentiation (LTP), termed LTP1 and LTP2. We have compared the susceptibility of these three types of synaptic plasticity to depotentiation, induced by low frequency stimulation (LFS; 2?Hz for 10?min) at the Schaffer collateral-commissural pathway in area CA1 of adult rat hippocampal slices. In interleaved experiments, STP and LTP were induced by three episodes of either compressed or spaced TBS (cTBS or sTBS). LFS had a more pronounced effect on the LTP induced by the cTBS. One traditional interpretation of these results is a difference in the time-dependent immunity against depotentiation. We suggest an alternative explanation: LFS rapidly reverses STP to reveal a slowly developing LTP. The cTBS protocol induces LTP1 that is moderately sensitive to depotentiation. The sTBS induces an additional component of LTP (LTP2) that is resistant to depotentiation.
Project description: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.
Project description:Long-term potentiation (LTP) at hippocampal CA1 synapses can be expressed by an increase either in the number (N) of AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors or in their single channel conductance (?). Here, we have established how these distinct synaptic processes contribute to the expression of LTP in hippocampal slices obtained from young adult rodents. LTP induced by compressed theta burst stimulation (TBS), with a 10?s inter-episode interval, involves purely an increase in N (LTP<sub>N</sub>). In contrast, either a spaced TBS, with a 10?min inter-episode interval, or a single TBS, delivered when PKA is activated, results in LTP that is associated with a transient increase in ? (LTP<sub>?</sub>), caused by the insertion of calcium-permeable (CP)-AMPA receptors. Activation of CaMKII is necessary and sufficient for LTP<sub>N</sub> whilst PKA is additionally required for LTP<sub>?</sub>. Thus, two mechanistically distinct forms of LTP co-exist at these synapses.
Project description:Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.
Project description:The Ts65Dn mouse is the most studied animal model of Down syndrome. Past research has shown a significant reduction in CA1 hippocampal long-term potentiation (LTP) induced by theta-burst stimulation (TBS), but not in LTP induced by high-frequency stimulation (HFS), in slices from Ts65Dn mice compared with euploid mouse-derived slices. Additionally, therapeutically relevant doses of the drug memantine were shown to rescue learning and memory deficits in Ts65Dn mice. Here, we observed that 1??M memantine had no detectable effect on HFS-induced LTP in either Ts65Dn- or control-derived slices, but it rescued TBS-induced LTP in Ts65Dn-derived slices to control euploid levels. Then, we assessed LTP induced by four HFS (4xHFS) and found that this form of LTP was significantly depressed in Ts65Dn slices when compared with LTP in euploid control slices. Memantine, however, did not rescue this phenotype. Because 4xHFS-induced LTP had not yet been characterized in Ts65Dn mice, we also investigated the effects of picrotoxin, amyloid beta oligomers, and soluble recombinant human prion protein (rPrP) on this form of LTP. Whereas ?10??M picrotoxin increased LTP to control levels, it also caused seizure-like oscillations. Neither amyloid beta oligomers nor rPrP had any effect on 4xHFS-induced LTP in Ts65Dn-derived slices.