LTP) And Depression Research Articles

Palmitoylation of A-Kinase Anchoring Protein 79/150 Regulates Dendritic Endosomal Targeting and Synaptic Plasticity Mechanisms

NMDA receptor-dependent long-term potentiation (LTP) and depression (LTD) are forms of synaptic plasticity underlying learning and memory that are expressed through increases and decreases, respectively, in dendritic spine size and AMPA receptor (AMPAR) phosphorylation and postsynaptic localization. The A-kinase anchoring protein 79/150 (AKAP79/150) signaling scaffold regulates AMPAR phosphorylation, channel activity, and endosomal trafficking associated with LTP and LTD. AKAP79/150 is targeted to dendritic spine plasma membranes by an N-terminal polybasic domain that binds phosphoinositide lipids, F-actin, and cadherin cell adhesion molecules. However, we do not understand how regulation of AKAP targeting controls AMPAR endosomal trafficking. Here, we report that palmitoylation of the AKAP N-terminal polybasic domain targets it to postsynaptic lipid rafts and dendritic recycling endosomes. AKAP palmitoylation was regulated by seizure activity in vivo and LTP/LTD plasticity-inducing stimuli in cultured rat hippocampal neurons. With chemical LTP induction, we observed AKAP79 dendritic spine recruitment that required palmityolation and Rab11-regulated endosome recycling coincident with spine enlargement and AMPAR surface delivery. Importantly, a palmitoylation-deficient AKAP79 mutant impaired regulation of spine size, endosome recycling, AMPAR trafficking, and synaptic potentiation. These findings emphasize the emerging importance of palmitoylation in controlling synaptic function and reveal novel roles for the AKAP79/150 signaling complex in dendritic endosomes.

A frontier in the understanding of synaptic plasticity: Solving the structure of the postsynaptic density

The postsynaptic density (PSD) is a massive multi-protein complex whose functions include positioning signalling molecules for induction of long-term potentiation (LTP) and depression (LTD) of synaptic strength. These processes are thought to underlie memory formation. To understand how the PSD coordinates bidirectional synaptic plasticity with different synaptic activation patterns, it is necessary to determine its three-dimensional structure. A structural model of the PSD is emerging from investigation of its molecular composition and connectivity, in addition to structural studies at different levels of resolution. Technical innovations including mass spectrometry of cross-linked proteins and super-resolution light microscopy can drive progress. Integrating different information relating to PSD structure is challenging since the structure is so large and complex. The reconstruction of a PSD subcomplex anchored by AKAP79 exemplifies on a small scale how integration can be achieved. With its entire molecular structure coming into focus, this is a unique opportunity to study the PSD.

Plasticity of motor threshold and motor-evoked potential amplitude – A model of intrinsic and synaptic plasticity in human motor cortex?

BackgroundNeuronal plasticity is the physiological correlate of learning and memory. In animal experiments, synaptic (i.e. long-term potentiation (LTP) and depression (LTD)) and intrinsic plasticity are distinguished. In human motor cortex, cortical plasticity can be demonstrated using transcranial magnetic stimulation (TMS). Changes in motor-evoked potential (MEP) amplitudes most likely represent synaptic plasticity and are thus termed LTP-like and LTD-like plasticity. Objective/hypothesisWe investigated the role of changes of motor threshold and their relation to changes of MEP amplitudes. MethodsWe induced plasticity by paired associative stimulation (PAS) with 25 ms or 10 ms inter-stimulus interval or by motor practice (MP) in 64 healthy subjects aged 18–31 years (median 24.0). ResultsWe observed changes of MEP amplitudes and motor threshold after PAS[25], PAS[10] and MP. In all three protocols, long-term individual changes in MEP amplitude were inversely correlated to changes in motor threshold (PAS[25]: P = .003, n = 36; PAS[10]: P = .038, n = 19; MP: P = .041, n = 19). ConclusionWe conclude that changes of MEP amplitudes and MT represent two indices of motor cortex plasticity. Whereas increases and decreases in MEP amplitude are assumed to represent LTP-like or LTD-like synaptic plasticity of motor cortex output neurons, changes of MT may be considered as a correlate of intrinsic plasticity.

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.

Presynaptic LTP and LTD of Excitatory and Inhibitory Synapses

Ubiquitous forms of long-term potentiation (LTP) and depression (LTD) are caused by enduring increases or decreases in neurotransmitter release. Such forms or presynaptic plasticity are equally observed at excitatory and inhibitory synapses and the list of locations expressing presynaptic LTP and LTD continues to grow. In addition to the mechanistically distinct forms of postsynaptic plasticity, presynaptic plasticity offers a powerful means to modify neural circuits. A wide range of induction mechanisms has been identified, some of which occur entirely in the presynaptic terminal, whereas others require retrograde signaling from the postsynaptic to presynaptic terminals. In spite of this diversity of induction mechanisms, some common induction rules can be identified across synapses. Although the precise molecular mechanism underlying long-term changes in transmitter release in most cases remains unclear, increasing evidence indicates that presynaptic LTP and LTD can occur in vivo and likely mediate some forms of learning.

SAP97 directs NMDA receptor spine targeting and synaptic plasticity

SAP97 is a multidomain scaffold protein implicated in the forward trafficking and synaptic localization of NMDA- and AMPA-type glutamate receptors. Alternative splicing of SAP97 transcripts gives rise to palmitoylated αSAP97 and L27-domain containing βSAP97 isoforms that differentially regulate the subsynaptic localization of GluR1 subunits of AMPA receptors. Here, we examined whether SAP97 isoforms regulate the mechanisms underlying long-term potentiation (LTP) and depression (LTD) and find that both α- and β-forms of SAP97 impair LTP but enhance LTD via independent isoform-specific mechanisms. Live imaging of α- and βSAP97 revealed that the altered synaptic plasticity was not due to activity-dependent changes in SAP97 localization or exchange kinetics. However, by recording from pairs of synaptically coupled hippocampal neurons, we show that αSAP97 occludes LTP by enhancing the levels of postsynaptic AMPA receptors, while βSAP97 blocks LTP by reducing the synaptic localization of NMDA receptors. Examination of the surface pools of AMPA and NMDA receptors indicates that αSAP97 selectively regulates the synaptic pool of AMPA receptors, whereas βSAP97 regulates the extrasynaptic pools of both AMPA and NMDA receptors. Knockdown of βSAP97 increases the synaptic localization of both AMPA and NMDA receptors, showing that endogenous βSAP97 restricts glutamate receptor expression at excitatory synapses. This isoform-dependent differential regulation of synaptic versus extrasynaptic pools of glutamate receptors will determine how many receptors are available for the induction and the expression of synaptic plasticity. Our data support a model wherein SAP97 isoforms can regulate the ability of synapses to undergo plasticity by controlling the surface distribution of AMPA and NMDA receptors.

An abstract model of the basal ganglia, reward learning and action selection

Learning is of major interest for various fields, from human pathologies to artificial intelligence. Animal and biology experiments have provided a great amount of data in this area, especially in classical and operant conditioning. Reinforcement learning is largely used in computational models in order to reproduce and explain these observations. This method enables to model a wide range of phenomena from the neuronal level to the behavior of a whole organism. Studying how information about reward or punishment is processed in the brain is crucial in the understanding of the action selection and decision-making in normal and pathological conditions. Basal Ganglia are a group of nuclei playing a major role in processing motor, associative and limbic information [1] and could be specialized in resolving conflicts between these sub-systems that compete for access to limited cognitive ressources [2]. Dopaminergic neurons activity is believed to be related to the reward prediction error and is involved in long term potentiation (LTP) and depression (LTD) in the striatum [3]. We present here an abstract computational model of the Basal Ganglia using reinforcement learning and Bayesian inference. It is based on a dual pathway architecture similar to the direct / Go and indirect / NoGo pathways that have been found in biology [4]. The units could be seen as grandmother cells, with inputs consisting of states and outputs being actions. Thus as a result of the activity in both pathways, an action will be selected based on the state and the previous outcomes of the different actions when dealing with the same state, that is if a reward has been obtained or not. One aim of our model is to be biologically plausible, weights can be updated via a triple activation Hebbian learning rule, similar to pre-synaptic activity, post-synaptic depolarisation and dopamine level [5]. The update equation is based on the probability of co-activity of the different active units. In its current form, the model uses trace activation and a simple delay mechanism. Basically, when a reward occurs, the weight between the active units is increased in the Go projection while it is decreased in the NoGo connection. In a one to one mapping learning scheme (only one specific action for a given state triggers a reward), the simulation shows good results in both learning and re-learning, i.e. the mapping is then shuffled. One interesting feature is the homeostasis property of the units: the variations of the sum of the outgoing and ingoing weights and bias, of a particular unit, are very small. In constrained set up (low numbers of possible actions and states), similar to experimental design, learning in stochastic reward occurrence is handled and the results are similar to the data. The response of midbrain dopamine neurons is positively correlated with the number of unrewarded trials [6] and our model produces a similar result with the prediction-error value. Future works will focus on reproducing conditioning phenomena and implementing spiking neurons.

Erythropoietin decreases the excitatory neurotransmitter release probability and enhances synaptic plasticity in mice hippocampal slices

In order to examine the direct acute effect of erythropoietin (EPO) perfusion on synaptic plasticity and transmitter release probability in hippocampal slices, one month old mice were decapitated and hippocampal slices were prepared. The effect of EPO perfusion (50 U/ml) on the basic synaptic transmission of hippocampal slices was examined. In addition, paired-pulse facilitation (PPF with inter stimulus intervals ISI of 50, 100 and 200 ms), long term potentiation (LTP) and depression (LTD) were recorded using high (HFS) and low (LFS) frequency stimulations. EPO-perfusion depressed significantly the slope of the fEPSP. The PPF ratio was increased significantly when compared with pre-EPO-perfusion. Stimulation of the control slices with LFS (1 Hz) depressed significantly the slope of the fEPSP (77.7 ± 3.85% of the baseline responses). Intermediate stimulation frequency (10 Hz) produced no significant changes, while HFS (100 Hz) induced significant potentiation of the responses (142.38 ± 7.72%). In EPO-perfused slices significant bigger responses were obtained (1 Hz, 101.12 ± 5.69%, 10 Hz, 123.24 ± 2.68, and 100 Hz, 216.41 ± 20.1) when compared to the control slices. These results suggest that erythropoietin decreases the excitatory neurotransmitter release probability and may in this way protect the synapses from toxic levels of glutamate. Erythropoietin perfusion increased the expression of long-term potentiation in the hippocampus which is considered as basic cellular model for learning and memory.

Altered Bidirectional Plasticity and Reduced Implicit Motor Learning in Concussed Athletes

Persistent motor/cognitive alterations and increased prevalence of Alzheimer's disease are known consequences of recurrent sports concussions, the most prevalent cause of mild traumatic brain injury (TBI) among youth. Animal models of TBI demonstrated that impaired learning was related to persistent synaptic plasticity suppression in the form of long-term potentiation (LTP) and depression (LTD). In humans, single and repeated concussive injuries lead to lifelong and cumulative enhancements of gamma-aminobutyric acid (GABA)-mediated inhibition, which is known to suppress LTP/LTD plasticity. To test the hypothesis that increased GABAergic inhibition after repeated concussions suppresses LTP/LTD and contributes to learning impairments, we used a paired associative stimulation (PAS) protocol to induce LTP/LTD-like effects in primary motor cortex (M1) jointly with an implicit motor learning task (serial reaction time task, SRTT). Our results indicate that repeated concussions induced persistent elevations of GABA(B)-mediated intracortical inhibition in M1, which was associated with suppressed PAS-induced LTP/LTD-like synaptic plasticity. This synaptic plasticity suppression was related to reduced implicit motor learning on the SRTT task relative to normal LTP/LTD-like synaptic plasticity in unconcussed teammates. These findings identify GABA neurotransmission alterations after repeated concussions and suggest that impaired learning after multiple concussions could at least partly be related to compromised GABA-dependent LTP/LTD synaptic plasticity.

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.

The Many Forms and Functions of Long Term Plasticity at GABAergic Synapses

On February 12th 1973, Bliss and Lomo submitted their findings on activity-dependent plasticity of glutamatergic synapses. After this groundbreaking discovery, long-term potentiation (LTP) and depression (LTD) gained center stage in the study of learning, memory, and experience-dependent refinement of neural circuits. While LTP and LTD are extensively studied and their relevance to brain function is widely accepted, new experimental and theoretical work recently demonstrates that brain development and function relies on additional forms of plasticity, some of which occur at nonglutamatergic synapses. The strength of GABAergic synapses is modulated by activity, and new functions for inhibitory synaptic plasticity are emerging. Together with excitatory neurons, inhibitory neurons shape the excitability and dynamic range of neural circuits. Thus, the understanding of inhibitory synaptic plasticity is crucial to fully comprehend the physiology of brain circuits. Here, I will review recent findings about plasticity at GABAergic synapses and discuss how it may contribute to circuit function.

Loss of topographic specificity of LTD-like plasticity is a trait marker in focal dystonia

In focal hand dystonia, long-term potentiation (LTP) and depression (LTD)-like neuronal plasticity, as assessed by paired associative stimulation (PAS) targeting the hand-associated motor cortex, is enhanced and the topographic organization of plasticity is lost. However, if any of these abnormalities alone is sufficient to cause focal dystonia (FD) remains unknown. Ten patients with cervical dystonia (CD), 9 with blepharospasm (BS) and 16 age- and sex-matched controls were examined. PAS was performed by combining repetitively electric stimulation of the median nerve with subsequent transcranial magnetic stimulation of the contralateral motor cortex at 21.5 ms (PAS21.5) and 10 ms (PAS10). Corticospinal excitability was indexed by the magnitude of motor evoked potentials (MEPs) recorded from abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. In controls, MEP size of the homotopically conditioned APB increased after PAS21.5 whereas the MEP size of the heterotopically conditioned ADM remained stable. PAS10 led to a decrease of MEP size of the APB and to an increase of the heterotopic ADM. In contrast, after PAS21.5 and PAS10 in CD and BS MEP size increased and decreased, respectively, in both muscles. The magnitude of excitability changes, however, did not differ between dystonic patients and healthy controls. In FD the topographic organization of PAS21.5 and PAS10-induced plasticity is deranged in cortical areas not involved in the control of the dystonic body part. Somatotopical disorganization of plasticity may represent an endophenotypic trait in FD but may not be sufficient to generate a dystonic phenotype. Development of a dystonic phenotype may require that the gain of plasticity is additionally enhanced. This article is part of a Special Issue entitled “Advances in dystonia”.

Postnatal alterations in induction threshold and expression magnitude of long‐term potentiation and long‐term depression at hippocampal synapses

Activity-dependent synaptic plasticity refines neural networks during development and subserves information processing in adulthood. Previous research has revealed postnatal alterations in synaptic plasticity at nearly all forebrain synapses, suggesting different forms of synaptic plasticity may contribute to network development and information processing. To assess possible relationships between modifications in synaptic plasticity and maturation of cognitive ability, we examined excitatory synaptic function in area CA1 of the mouse hippocampus ∼3 weeks of age, when hippocampal-dependent learning and memory abilities first emerge. Long-term potentiation (LTP) and depression (LTD) of synaptic efficacy were observed in slices from juvenile animals younger than 3 weeks of age. Both pre- and postsynaptic mechanisms supported LTP and LTD in juveniles. After the third postnatal week, the magnitude of LTP was reduced and the threshold for postsynaptic induction was reduced, but the threshold for presynaptic induction was increased. The reduced threshold for postsynaptic LTP appeared to be due, partly, to an increase in baseline excitatory synaptic strength, which likely permitted greater postsynaptic depolarization during induction. Low frequency stimulation did not induce LTD at this more mature stage, but it blocked subsequent induction of LTP, suggesting metaplastic differences across age groups. Late postnatal modifications in activity-dependent synaptic plasticity might reflect attenuation of mechanisms more closely tied to network formation (presynaptic potentiation and pre- and postsynaptic depression) and unmasking of mechanisms underlying information processing and storage (associative postsynaptic potentiation), which likely impact the integrative capacity of the network and regulate the emergence of adult-like cognitive abilities.

Cell Type-Specific Long-Term Plasticity at Glutamatergic Synapses onto Hippocampal Interneurons Expressing either Parvalbumin or CB1Cannabinoid Receptor

Different GABAergic interneuron types have specific roles in hippocampal function, and anatomical as well as physiological features vary greatly between interneuron classes. Long-term plasticity of interneurons has mostly been studied in unidentified GABAergic cells and is known to be very heterogeneous. Here we tested whether cell type-specific plasticity properties in distinct GABAergic interneuron types might underlie this heterogeneity. We show that long-term potentiation (LTP) and depression (LTD), two common forms of synaptic plasticity, are expressed in a highly cell type-specific manner at glutamatergic synapses onto hippocampal GABAergic neurons. Both LTP and LTD are generated in interneurons expressing parvalbumin (PV+), whereas interneurons with similar axon distributions but expressing cannabinoid receptor-1 show no lasting plasticity in response to the same protocol. In addition, LTP or LTD occurs in PV+ interneurons with different efferent target domains. Perisomatic-targeting PV+ basket and axo-axonic interneurons express LTP, whereas glutamatergic synapses onto PV+ bistratified cells display LTD. Both LTP and LTD are pathway specific, independent of NMDA receptors, and occur at synapses with calcium-permeable (CP) AMPA receptors. Plasticity in interneurons with CP-AMPA receptors strongly modulates disynaptic GABAergic transmission onto CA1 pyramidal cells. We propose that long-term plasticity adjusts the synaptic strength between pyramidal cells and interneurons in a cell type-specific manner and, in the defined CA1 interneurons, shifts the spatial pattern of inhibitory weight from pyramidal cell dendrites to the perisomatic region.

Spike-timing dependent plasticity in inhibitory circuits

Inhibitory circuits in the brain rely on GABA-releasing interneurons. For long, inhibitory circuits were considered weakly plastic in the face of patterns of neuronal activity that trigger long-term changes in the synapses between excitatory principal cells. Recent studies however have shown that GABAergic circuits undergo various forms of long-term plasticity. For the purpose of this review, we identify three major long-term plasticity expression sites. The first locus is the glutamatergic synapses that excite GABAergic inhibitory cells and drive their activity. Such synapses, on many but not all inhibitory interneurons, exhibit long-term potentiation (LTP) and depression (LTD). Second, GABAergic synapses themselves can undergo changes in GABA release probability or postsynaptic GABA receptors. The third site of plasticity is in the postsynaptic anion gradient of GABAergic synapses; coincident firing of GABAergic axons and postsynaptic neurons can cause a long-lasting change in the reversal potential of GABAA receptors mediating fast inhibitory postsynaptic potentials. We review the recent literature on these forms of plasticity by asking how they may be triggered by specific patterns of pre- and postsynaptic action potentials, although very few studies have directly examined spike-timing dependent plasticity (STDP) protocols in inhibitory circuits. Plasticity of interneuron recruitment and of GABAergic signaling provides for a rich flexibility in inhibition that may be central to many aspects of brain function. We do not consider plasticity at glutamatergic synapses on Purkinje cells and other GABAergic principal cells.

Downregulation of GABA signaling enhances axonal rewiring and contributes to spontaneous recovery of motor functions after traumatic brain injury

Activity-dependent long-term potentiation (LTP) and depression (LTD) of synaptic strength underlie multiple forms of learning and memory. Spike-timing-dependent plasticity (STDP) has been described as a Hebbian synaptic learning rule that could account for experience-dependent changes in neural networks, but little is known about whether and how STDP evolves during development. We previously showed that GABAergic signaling governs STDP polarity and thus operates as a Hebbian/anti-Hebbian switch in the striatum. Although GABAergic networks are subject to important developmental maturation, it remains unclear whether STDP is developmentally shaped by GABAergic signaling. Here, we investigated whether STDP rules are developmentally regulated at corticostriatal synapses in the dorsolateral striatum. We found that striatal STDP displays unidirectional plasticity (Hebbian tLTD) in young rats (P7-10) whereas STDP is bidirectional and anti-Hebbian in juvenile (P20-25) and adult (P60-90) rats. We also provide evidence that the appearance of tonic (extrasynaptic) GABAergic signaling from the juvenile stage is a crucial factor in shaping STDP rules during development, establishing bidirectional anti-Hebbian STDP in the adult striatum. Thus, developmental maturation of GABAergic signaling tightly drives the polarity of striatal plasticity.

Role of Specific Synaptic Plasticity Interfering Peptides in the Expression of Morphine Induced Conditioned Place Preference in Mice

Learned association between context and drug abuse is essential for the drug conditioned place preference (CPP), which is an animal model widely used to measure drug reward. Synaptic plasticity, in the form of long-term potentiation (LTP) and depression (LTD), is regarded as a proposed cellular substrate of learning and memory. However, the exact role of LTP/LTD in addiction is not known yet. Therefore, by bioinformatics we designed peptides aiming to interfere with LTP and LTD respectively, to study their individual role in the expression of morphine CPP. We found that the interfering peptide Pep-A2 can specifically block hippocampal LTP in CA1 region, whereas Pep-A3 can block LTD in this region. Treatment of either of their cell penetrating forms (Tat-A2 or Tat-A3) before test can block the expression of Morphine CPP in mice. These results suggested that both LTP and LTD are required in the drug-associated learning and memory.

Dissecting cooperative calmodulin binding to CaM kinase II: a detailed stochastic model

Calmodulin (CaM) is a major Ca(2+) binding protein involved in two opposing processes of synaptic plasticity of CA1 pyramidal neurons: long-term potentiation (LTP) and depression (LTD). The N- and C-terminal lobes of CaM bind to its target separately but cooperatively and introduce complex dynamics that cannot be well understood by experimental measurement. Using a detailed stochastic model constructed upon experimental data, we have studied the interaction between CaM and Ca(2+)-CaM-dependent protein kinase II (CaMKII), a key enzyme underlying LTP. The model suggests that the accelerated binding of one lobe of CaM to CaMKII, when the opposing lobe is already bound to CaMKII, is a critical determinant of the cooperative interaction between Ca(2+), CaM, and CaMKII. The model indicates that the target-bound Ca(2+) free N-lobe has an extended lifetime and may regulate the Ca(2+) response of CaMKII during LTP induction. The model also reveals multiple kinetic pathways which have not been previously predicted for CaM-dissociation from CaMKII.

N-Methyl-d-aspartate Receptors Mediate the Phosphorylation and Desensitization of Muscarinic Receptors in Cerebellar Granule Neurons

Changes in synaptic strength mediated by ionotropic glutamate N-methyl-d-asparate (NMDA) receptors is generally considered to be the molecular mechanism underlying memory and learning. NMDA receptors themselves are subject to regulation through signaling pathways that are activated by G-protein-coupled receptors (GPCRs). In this study we investigate the ability of NMDA receptors to regulate the signaling of GPCRs by focusing on the Gq/11-coupled M3-muscarinic receptor expressed endogenously in mouse cerebellar granule neurons. We show that NMDA receptor activation results in the phosphorylation and desensitization of M3-muscarinic receptors through a mechanism dependent on NMDA-mediated calcium influx and the activity of calcium-calmodulin-dependent protein kinase II. Our study reveals a complex pattern of regulation where GPCRs (M3-muscarinic) and NMDA receptors can feedback on each other in a process that is likely to influence the threshold value of signaling networks involved in synaptic plasticity.

The N-methyl-d-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats

NMDA receptor (NMDAR) activity has been strongly implicated in both in vitro and in vivo learning models and the decline in cognitive function associated with aging and is linked to a decrease in NMDAR functional expression. GLYX-13 is a tetrapeptide (Thr-Pro-Pro-Thr) which acts as a NMDAR receptor partial agonist at the glycine site. GLYX-13 was administered to young adult (3 months old) and aged (27-32 months old) Fischer 344 X Brown Norway F1 rats (FBNF1), and behavioral learning tested in trace eye blink conditioning (tEBC), a movable platform version of the Morris water maze (MWM), and alternating t-maze tasks. GLYX-13 (1mg/kg, i.v.) enhanced learning in both young adult and aging animals for MWM and alternating t-maze, and increased tEBC in aging rats. We previously showed optimal enhancement of tEBC in young adult rats given GLYX-13 at the same dose. Of these learning tasks, the MWM showed the most robust age related deficit in learning. In the MWM, GLYX-13 enhancement of learning was greater in the old compared to the young adult animals. Examination of the induction of long-term potentiation (LTP) and depression (LTD) at Schaffer collateral-CA1 synapses in hippocampal slices showed that aged rats showed marked, selective impairment in the magnitude of LTP evoked by a sub-maximal tetanus, and that GLYX-13 significantly enhanced the magnitude of LTP in slices from both young adult and aged rats without affecting LTD. These data, combined with the observation that the GLYX-13 enhancement of learning was greater in old than in young adult animals, suggest that GLYX-13 may be a promising treatment for deficits in cognitive function associated with aging.