Forms Of Synaptic Plasticity Research Articles

Diacylglycerol Kinases in the Coordination of Synaptic Plasticity.

Synaptic plasticity is activity-dependent modification of the efficacy of synaptic transmission. Although, detailed mechanisms underlying synaptic plasticity are diverse and vary at different types of synapses, diacylglycerol (DAG)-associated signaling has been considered as an important regulator of many forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Recent evidences indicate that DAG kinases (DGKs), which phosphorylate DAG to phosphatidic acid to terminate DAG signaling, are important regulators of LTP and LTD, as supported by the results from mice lacking specific DGK isoforms. This review will summarize these studies and discuss how specific DGK isoforms distinctly regulate different forms of synaptic plasticity at pre- and postsynaptic sites. In addition, we propose a general role of DGKs as coordinators of synaptic plasticity that make local synaptic environments more permissive for synaptic plasticity by regulating DAG concentration and interacting with other synaptic proteins.

The GABAA receptor agonist muscimol induces an age- and region-dependent form of long-term depression in the mouse striatum.

Several forms of long-term depression (LTD) of glutamatergic synaptic transmission have been identified in the dorsal striatum and in the nucleus accumbens (NAc). Such experience-dependent synaptic plasticity might play important roles in reward-related learning. The GABAA receptor agonist muscimol was recently found to trigger a long-lasting depression of glutamatergic synaptic transmission in the NAc of adolescent mice, but the mechanisms that underlie this novel form of LTD were not studied. Here we examined the effect of muscimol applied in the perfusion solution on the amplitude of field excitatory postsynaptic potentials/population spikes (fEPSP/PSs) in mouse brain slices. We found that muscimol depressed the fEPSP/PS in the NAc of adolescent mice but not adult mice, through both postsynaptic and presynaptic mechanisms. Indeed, muscimol altered the fEPSP/PS paired-pulse ratio, depolarized the membrane of projection neurons, and decreased the frequency, but not amplitude, of spontaneous excitatory postsynaptic currents in the NAc of adolescent mice. The LTD induced by muscimol likely involved endocannabinoids, metabotropic glutamate receptors (mGluRs), but not TRPV1 receptors. Muscimol-LTD was occluded by prior induction of LTD through low-frequency stimulation (LFS) of the slice, demonstrating a common pathway in the induction of LFS-LTD and muscimol-LTD. We also found that muscimol induced a form of LTD in the dorsolateral striatum of adult but not adolescent mice. This LTD was mediated by endocannabinoids but did not involve mGluRs or TRPV1 receptors. These results identify a novel form of synaptic plasticity, and its mechanisms of induction, which is age and region dependent. These findings may contribute to a better understanding of the increased susceptibility of the adolescent brain to long-term synaptic changes in regions associated with reward mechanisms.

Synaptic GluN2B/CaMKII-α Signaling Induces Synapto-Nuclear Transport of ERK and Jacob.

A central pathway in synaptic plasticity couples N-Methyl-D-Aspartate-receptor (NMDAR)-signaling to the activation of extracellular signal-regulated kinases (ERKs) cascade. ERK-dependency has been demonstrated for several forms of synaptic plasticity as well as learning and memory and includes local synaptic processes but also long-distance signaling to the nucleus. It is, however, controversial how NMDAR signals are connected to ERK activation in dendritic spines and nuclear import of ERK. The synapto-nuclear messenger Jacob couples NMDAR-dependent Ca2+-signaling to CREB-mediated gene expression. Protein transport of Jacob from synapse to nucleus essentially requires activation of GluN2B-containing NMDARs. Subsequent phosphorylation and binding of ERK1/2 to and ERK-dependent phosphorylation of serine 180 in Jacob encodes synaptic but not extrasynaptic NMDAR activation. In this study we show that stimulation of synaptic NMDAR in hippocampal primary neurons and induction of long-term potentiation (LTP) in acute slices results in GluN2B-dependent activation of CaMKII-α and subsequent nuclear import of active ERK and serine 180 phosphorylated Jacob. On the contrary, no evidence was found that either GluN2A-containing NMDAR or RasGRF2 are upstream of ERK activation and nuclear import of Jacob and ERK.

Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling

Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra-syndrome-associated protein EHMT1 plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both invitro and invivo. Our findings suggest that H3K9me2-mediated changes in chromatin structure govern a repressive program that controls synaptic scaling.

Transcriptional regulation of long-term potentiation.

Long-term potentiation (LTP), the persistent strengthening of synapses following high levels of stimulation, is a form of synaptic plasticity that has been studied extensively as a possible mechanism for learning and memory formation. The strengthening of the synapse that occurs during LTP requires cascades of complex molecular processes and the coordinated remodeling of pre-synaptic and post-synaptic neurons. Despite over four decades of research, our understanding of the transcriptional mechanisms and molecular processes underlying LTP remains incomplete. Identification of all the proteins and non-coding RNA transcripts expressed during LTP may provide greater insight into the molecular mechanisms involved in learning and memory formation.

Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.

The anterior cingulate cortex (ACC) is activated in both acute and chronic pain. In this Review, we discuss increasing evidence from rodent studies that ACC activation contributes to chronic pain states and describe several forms of synaptic plasticity that may underlie this effect. In particular, one form of long-term potentiation (LTP) in the ACC, which is triggered by the activation of NMDA receptors and expressed by an increase in AMPA-receptor function, sustains the affective component of the pain state. Another form of LTP in the ACC, which is triggered by the activation of kainate receptors and expressed by an increase in glutamate release, may contribute to pain-related anxiety.

Expression of nuclear Methyl-CpG binding protein 2 (Mecp2) is dependent on neuronal stimulation and application of Insulin-like growth factor 1

Methyl-CpG binding protein 2 (MECP2) is a chromosome-binding protein that regulates the development and maintenance of brain circuits. Altered function of the protein product of MECP2 plays an important role in the etiology of many neurodevelopmental disorders. Mutations involving a loss of function are implicated in the etiology of Rett syndrome, intellectual disability, psychosis and severe encephalopathy. Conversely, MECP2 duplications have been identified in autism and intellectual disability. MECP2 action is dependent on neuronal function, as the DNA binding is modulated by activity, and it is phosphorylated in response to stimulation. Although MECP2 is considered a major risk factor for neurodevelopmental disorders, and it is a mediator of activity-dependent mechanisms, the expression levels in response to neuronal activity have never been measured.We studied the expression of Mecp2 protein and RNA in mice neuronal cultures in response to different stimulation conditions and in the presence of insulin-like growth factor1 (IGF1): a growth factor involved in brain development and plasticity. The stimulation protocols were selected according to their ability to induce different forms of synaptic plasticity: rapid depolarization, feed-forward plasticity (LTP, LTD) and feedback forms of plasticity (TTX, KCl). We find a significant reduction of Mecp2 protein nuclear expression in neurons in response to stimuli that induce a potentiation of neuronal response, suggesting that Mecp2 protein expression is modulated by neuronal activation. Application of IGF1 to the cultures induces an increase in the expression of Mecp2 transcript and nuclear Mecp2 protein in neurons.These results show that Mecp2 is responsive to neuronal stimulation and IGF1, and different stimuli have different effects on Mecp2 expression; this differential response may have downstream effects on functional mechanisms regulating brain development and plasticity.

Acid-sensing ion channel 1a contributes to hippocampal LTP inducibility through multiple mechanisms.

The exact roles of acid-sensing ion channels (ASICs) in synaptic plasticity remain elusive. Here, we address the contribution of ASIC1a to five forms of synaptic plasticity in the mouse hippocampus using an in vitro multi-electrode array recording system. We found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region. However, these treatments did not affect hippocampal long-term depression induced by low frequency electrical stimulation or (RS)-3,5-dihydroxyphenylglycine. We also show that ASIC1a exerts its action in hippocampal LTP through multiple mechanisms that include but are not limited to augmentation of NMDA receptor function. Taken together, these results reveal new insights into the role of ASIC1a in hippocampal synaptic plasticity and the underlying mechanisms. This unbiased study also demonstrates a novel and objective way to assay synaptic plasticity mechanisms in the brain.

Orexin A induces bidirectional modulation of synaptic plasticity: Inhibiting long-term potentiation and preventing depotentiation

The orexin system consists of two peptides, orexin A and B and two receptors, OX1R and OX2R. It is implicated in learning and memory regulation while controversy remains on its role in modulating hippocampal synaptic plasticity in vivo and in vitro. Here, we investigated effects of orexin A on two forms of synaptic plasticity, long-term potentiation (LTP) and depotentiation of field excitatory postsynaptic potentials (fEPSPs), at the Schaffer Collateral-CA1 synapse of mouse hippocampal slices. Orexin A (≧30 nM) attenuated LTP induced by theta burst stimulation (TBS) in a manner antagonized by an OX1R (SB-334867), but not OX2R (EMPA), antagonist. Conversely, at 1 pM, co-application of orexin A prevented the induction of depotentiation induced by low frequency stimulation (LFS), i.e. restoring LTP. This re-potentiation effect of sub-nanomolar orexin A occurred at LFS of 1 Hz, but not 2 Hz, and with LTP induced by either TBS or tetanic stimulation. It was significantly antagonized by SB-334867, EMPA and TCS-1102, selective OX1R, OX2R and dual OXR antagonists, respectively, and prevented by D609, SQ22536 and H89, inhibitors of phospholipase C (PLC), adenylyl cyclase (AC) and protein kinase A (PKA), respectively. LFS-induced depotentiation was antagonized by blockers of NMDA, A1-adenosine and type 1/5 metabotropic glutamate (mGlu1/5) receptors, respectively. However, orexin A (1 pM) did not affect chemical-induced depotentiation by agonists of these receptors. These results suggest that orexin A bidirectionally modulates hippocampal CA1 synaptic plasticity, inhibiting LTP via OX1Rs at moderate concentrations while inducing re-potentiation via OX1Rs and OX2Rs, possibly through PLC and AC-PKA signaling at sub-nanomolar concentrations.

Enhanced long-term potentiation in mature rats in a model of epileptic spasms with betamethasone-priming and postnatal N-methyl-D-aspartate administration.

Patients with epileptic spasms are at high risk for learning and memory impairment later in life. We examined whether synaptic plasticity is affected in the adult hippocampus, a structure responsible for learning and memory, using an animal model of epileptic spasms of unknown cause. We produced a rat model of N-methyl-d-aspartate (NMDA)-induced spasms combined with prenatal betamethasone administration. In 6- to 11-week-old rats, we evaluated the long-term potentiation (LTP) and general properties of synaptic transmission in pyramidal neurons in the CA1 area of the hippocampus in brain slices. The magnitude of LTP by theta burst stimulation was significantly larger in adult rats with a history of infantile NMDA injections than in control rats and rats that received additional adrenocorticotropic hormone (ACTH) treatment. The frequency of spontaneous excitatory transmission, but not inhibitory transmission, was smaller in adult rats with a history of infantile NMDA injections. This study is the first to provide a basis for the alteration of synaptic plasticity and transmission in a model of epileptic spasms of unknown cause. Postnatal NMDA treatment causing epileptic spasms-like aberrant episodes in the early stage of life in rats has a latent influence on various forms of synaptic plasticity in the hippocampus. Our results provide a novel insight into cognitive impairment that appears later in life in patients with a history of epileptic spasms.

Effect of Neonatal Seizures on the Synaptic Plasticity of Rat Somatosensory Cortex

Using an experimental model of neonatal recurrent seizures, we investigated the influence of epileptic seizures on the various forms of synaptic plasticity in neurons of the somatosensory cortex. We have found that early seizures do not affect the post-tetanic potentiation of the amplitude of the postsynaptic potentials and the depression of postsynaptic potentials during high-frequency stimulation. However, they result in the chronic increase in the long-term potentiation of synaptic transmission. The changes in synaptic plasticity may affect the processing of the sensory information in patients with a history of recurrent seizures during early development.

Molecular mechanisms of autism as a form of synaptic dysfunction

Autism spectrum disorders are a separate group of defects with a very high genetic component. Genetic screening has identified hundreds of mutations and other genetic variations associated with autism, and bioinformatic analysis of signaling pathways and gene networks has led to understanding that many of these mutational changes are involved in the functioning of synapses. A synapse is a site of electrochemical communication between neurons and an essential subunit for learning and memory. Interneuronal communicative relationships are plastic. The most prominent forms of synaptic plasticity are accompanied by changes in protein biosynthesis, both in neuron body and in dendrites. Protein biosynthesis or translation is a carefully regulated process, with a central role played by mTOR (mammalian or mechanistic target of rapamycin). Normally mTOR-regulated translation is slightly inhibited, and in most cases mutational damage to at least one of the links of the mTOR signaling pathway, increases translation and leads to impaired synaptic plasticity and behavior. Deregulation of the local translation in dendrites is connected with the following monogenic autism spectrum disorders: neurofibromatosis type 1, Noonan syndrome, Costello syndrome, Cowden syndrome, tuberous sclerosis, fragile X chromosome, syndrome, and Rett syndrome. The review considers the most important mutations leading to monogenic autism, as well as the possibility of a mechanism-based treatment of certain disorders of the autism spectrum.

Auxiliary Subunit GSG1L Acts to Suppress Calcium-Permeable AMPA Receptor Function.

Calcium-permeable AMPA receptors (CP-AMPARs) are an important group of receptors for the neurotransmitter glutamate. These receptors contribute to various forms of synaptic plasticity, and alterations in their expression or regulation are also seen in a number of serious neurological conditions, including stroke, motor neuron disease, and cocaine addiction. Several groups of auxiliary transmembrane proteins have been described that enhance the function and cell-surface expression of AMPARs. We now report that the recently identified auxiliary protein GSG1L decreases weighted mean channel conductance and calcium permeability of CP-AMPARs while increasing polyamine-dependent rectification by diminishing outward current. Our experiments reveal that GSG1L is an auxiliary subunit that can markedly suppress CP-AMPAR function, in both recombinant systems and central neurons.

Robustness of spatial learning in flickering networks

It is widely accepted that the network of the hippocampal place cells provides a substrate of the of the environment. However, thousands of hippocampal neurons die every day and the networks formed by these cells constantly change due to various forms of synaptic plasticity. What then explains the remarkable reliability of our spatial memories? We propose a computational approach to answering this question based on a couple of insights. First, we propose that the hippocampal cognitive map is fundamentally topological, i.e., more similar to a subway map than to a topographical city map [1], and hence it is amenable to analysis by topological methods [2,3]. We then apply several novel methods from homology theory, to understand how dynamic connections between cells influences the speed and reliability of spatial learning. We simulate the rat's exploratory movements through different environments and study how topological invariants (stable topological features of different experimental environments) arise in a network of simulated neurons with dynamic, flickering connectivity. We find that despite transient connectivity the network of place cells produces a stable representation of the topology of the environment.

Extending computational models of astrocyte-neuron interactions with biochemical mechanisms on the postsynaptic terminal

There is increasing evidence that astrocytes not only interact with each other but also with adjacent neurons in the neural circuitry in a variety of brain areas. Many biophysical and biochemical mechanisms have been proposed to explain these interactions in vitro. Based on the experimental literature, the mechanisms involved seem to depend not only on the developmental stage of an animal but also on the brain area, neural circuitry, as well as on the experimental technique used to characterize the phenomena. Using biophysically and biochemically detailed compartmental models, we are interested in understanding how these interactions between neurons and astrocytes may regulate information processing and, notably, different forms of synaptic plasticity [1]. In this study, we designed a new model of the so-called tripartite synapse. The tripartite synapse is a concept of synaptic physiology in which there are three parts of a synapse: the presynaptic and postsynaptic terminals, and an astrocyte in between them [2]. Many previous studies in vitro have shown that gliotransmitters like glutamate are released from astrocytes into the synaptic cleft following activation of presynaptic or postsynaptic terminals, or activation of the astrocyte itself [3]. However, none of the previous modeling studies incorporate all features necessary to understand the complex interactions in full detail. We extend beyond these previously published fundamental, yet relatively simplistic representations (see, e.g., [4]). We describe the postsynaptic terminal using a two-compartmental approach, in addition to the presynaptic terminal and the astrocyte. We specifically address the postsynaptic mechanisms and their role in activating astrocytic calcium signaling and subsequent gliotransmission. By introducing realistic model components on the postsynaptic terminal, such as voltage-dependent receptor channels and the G-protein activated signaling cascades, we observe stimulus-dependent changes in astrocyte calcium oscillations leading to activation of not only astrocytes, but also of adjacent neurons. The long-term goal of our work is to develop detailed models of astrocyte-neuron interactions for different brain areas which allow testing experimentally evoked hypothesis, as well as some controversies in the field (see, e.g., [5]). These models will open up new avenues to assess the effects of numerous mechanisms of astrocytes on the dynamics of local neuronal networks. Only through systematic integration of in vitro and in silico work will we be able to understand how astrocytes may contribute to brain information processing and plasticity.

Acetylcholine Facilitates a Depolarization-Induced Enhancement of Inhibition in Rat CA1 Pyramidal Neurons

Cholinergic mechanisms in the hippocampus regulate forms of synaptic plasticity linked with cognition and spatial navigation, but the underlying mechanisms remain largely unknown. Here, in rat hippocampal CA1 pyramidal cells under blockade of ionotropic glutamate receptors, we report that a single acetylcholine pulse and repeated depolarization activated a robust and enduring postsynaptic depolarization-induced enhancement of inhibition (DEI) that masked a presynaptic depolarization-induced suppression of inhibition (DSI). Increased cytosolic Ca2+ and M1-muscarinic receptor activation caused the rise in voltage-sensitive α5βγ2-containing γ-aminobutyric acid type-A receptors that generated DEI. In summary, this muscarinic-mediated activity-dependent plasticity rapidly transfers depolarization effects on inhibition from presynaptic suppression or DSI to postsynaptic enhancement or DEI, a change potentially relevant in behavior.

EFFECT OF NEONATAL SEIZURES ON THE SYNAPTIC PLASTICITY OF RAT SOMATOSENSORY CORTEX

Using an experimental model of neonatal recurrent seizures we investigated the influence of epileptic seizures in the various forms of synaptic plasticity in neurons of the somatosensory cortex. We found that early seizures do not affect the post-tetanic potentiation of the amplitude of the postsynaptic potentials and the depression of postsynaptic potentials during high-frequency stimulation. However they result in the chronic increase of the long-term potentiation of synaptic transmission. These changes of synaptic plasticity may affect the processing of the sensory information in patients with a history of recurrent seizures during early development.

The origin and diversity of PICK1 palmitoylation in the Eutheria

Glutamate is the major excitatory neurotransmitter in the vertebrate central nervous system. AMPA-type ionotoropic glutamate receptors (AMPA receptors) are responsible for the glutamate-mediated postsynaptic excitation of neurons. The trafficking of AMPA receptors into and out of synapses is highly dynamic and is regulated by various AMPA receptor-interacting proteins that bind to the cytoplasmic tail of the receptors. This process is regulated by palmitoylation of AMPA receptors and PDZ domain-containing AMPA receptor-interacting proteins, such as PSD-95 and GRIP1b. Post-translational protein palmitoylation is the only reversible covalent attachment of lipid to protein. Protein interacting with C-kinase 1 (PICK1) is an AMPA receptor-interacting protein, associating directly with the C-termini of AMPA receptors through its PDZ domain. PICK1 has been shown to regulate the surface expression, trafficking, and synaptic targeting of AMPA receptors in several forms of synaptic plasticity. Our previous study revealed that post-translational protein palmitoylation of PICK1 C-terminus regulates PICK1-mediated internalization of AMPA receptors in mammalian neurons. In this report, I analyzed conservation and divergence of palmitoylation sites found in PICK1 orthologs. Analysis of databases revealed that the palmitoylation site of PICK1 has been broadly conserved during evolution in the eutherian (placental) lineage, whereas the corresponding sites are substituted in subclasses Prototheria (platypus) and Metatheria (Marsupialia) and exceptionally some species in Eutheria (Placentalia). This finding indicates that palmitoylation-dependent regulation mechanism of PICK1 was established much later than those of AMPA receptors and other PDZ domain-containing AMPA receptor-interacting proteins, which are completely conserved in all vertebrate species. PICK1-dependent dynamic trafficking of glutamatergic synapses made possible by this reversible palmitoylation of PICK1 C-terminus may be critical for the specific refined functions of complex placental nervous systems.

A novel form of synaptic plasticity in field CA3 of hippocampus requires GPER1 activation and BDNF release

A novel form of synaptic plasticity in field CA3 of hippocampus requires GPER1 activation and BDNF release

Evidence for glycinergic GluN1/GluN3 NMDA receptors in hippocampal metaplasticity

Hebbian, or associative, forms of synaptic plasticity are considered the molecular basis of learning and memory. However, associative synaptic modifications, including long-term potentiation (LTP) and depression (LTD), can form positive feedback loops which must be constrained for neural networks to remain stable. One proposed constraint mechanism is metaplasticity, a process whereby synaptic changes shift the threshold for subsequent plasticity. Metaplasticity has been functionally observed but the molecular basis is not well understood. Here, we report that stimulation which induces LTP recruits GluN2B-lacking GluN1/GluN3 NMDA receptors (NMDARs) to excitatory synapses of hippocampal pyramidal neurons. These unconventional receptors may compete against conventional GluN1/GluN2 NMDARs to favor synaptic depotentiation in response to subsequent “LTP-inducing” stimulation. These results implicate glycinergic GluN1/GluN3 NMDAR as molecular brakes on excessive synaptic strengthening, suggesting a role for these receptors in the brain that has previously been elusive.