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Results for “synaptic plasticity”

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At least 1,531 records · Page 85Linked to original sources

PubMed1999

Developmental exposure to a commercial PCB mixture (Aroclor 1254) produces a persistent impairment in long-term potentiation in the rat dentate gyrus in vivo.

Developmental exposure to polycholorinated biphenyls (PCBs) has been associated with cognitive deficits in humans and laboratory animals. The present study sought to examine synaptic plasticity in the hippocampus, a brain region critical for some types of memory function, in animals exposed to PCBs early in development. Pregnant Long-Evans rats were administered either corn oil (control) or 6 mg/kg/day of a commercial PCB mixture, Aroclor 1254 (A1254) by gavage from gestational day (GD) 6 until pups were weaned on postnatal day (PND) 21. In adult male offspring (3-6 months of age), field potentials evoked by perforant path stimulation were recorded in the dentate gyrus under urethane anesthesia. Input/output (I/O) functions were assessed by averaging the response evoked in the dentate gyrus to stimulus pulses delivered to the perforant path in an ascending intensity series. Long-term potentiation (LTP) was induced by delivering a series of brief high frequency (400 Hz) train bursts to the perforant path at a moderate stimulus intensity and I/O functions were reassessed 1 h later. No differences in baseline synaptic population spike (PS) and minor effects on excitatory postsynaptic potential (EPSP) slope amplitudes were discerned between the groups prior to train delivery. Post-train I/O functions, however, revealed a 50% decrement in the magnitude of LTP in PCB-exposed animals. These data are the first to demonstrate persistent decrements in hippocampal synaptic plasticity in the intact animal following developmental exposure to PCBs. Disruption of early brain ontogeny due to developmental PCB exposure may underlie perturbations in the neurological substrates that support synaptic plasticity and contribute to deficits in LTP and learning that persist into adulthood.

Action Potentials↗

PubMed2006

[Role of astrocytes in rewarding effects of drugs of abuse].

There are two categories of cells in the central nervous system; neurons and adjacent glial cells including astrocytes, microglia and oligodendrocytes. Accumulating evidence suggests that astrocytes actively participate in synaptic plasticity. On the other hand, long-term exposure to drugs of abuse could induce neuronal plasticity. Astrocytes undergo a process of prolifiration, morphological change, and enhancement of glial fibrillary acidic protein expression, termed activation of astrocytes. Recently, we demonstrated a dramatic increase in reactive astrocytes in the dorsal horn of the spinal cord following repeated in vivo treatment with morphine. We also found that in vivo treatment with morphine, which was associated with the rewarding effect, caused a robust astrocytic activation in the cingulate cortex. These data suggest that astrocytes may contribute to the synaptic plasticity induced by morphine during the development of dependence and tolerance. Therefore, this review focuses on several aspects of astrocytic response and discusses possible roles of astrocytes in the development of dependence and tolerance induced by morphine. We also report here that protein kinase C, Janus kinase/signal transducer and activator of transcription pathway, cyclin-dependent kinase 5 and tyrosine kinase cascade are directly involved in the neuron-glia communication during the development of synaptic plasticity induced by chronic morphine treatment.

Animals↗

PubMed2006

Transient calcium and dopamine increase PKA activity and DARPP-32 phosphorylation.

Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons of the striatum occurs when glutamatergic input (from cortex) and dopaminergic input (from substantia nigra) are received simultaneously. Subsequent to learning, medium spiny neurons with strengthened synapses are more likely to fire in response to cortical input alone. This synaptic plasticity is produced by phosphorylation of AMPA receptors, caused by phosphorylation of various signalling molecules. A key signalling molecule is the phosphoprotein DARPP-32, highly expressed in striatal medium spiny neurons. DARPP-32 is regulated by several neurotransmitters through a complex network of intracellular signalling pathways involving cAMP (increased through dopamine stimulation) and calcium (increased through glutamate stimulation). Since DARPP-32 controls several kinases and phosphatases involved in striatal synaptic plasticity, understanding the interactions between cAMP and calcium, in particular the effect of transient stimuli on DARPP-32 phosphorylation, has major implications for understanding reinforcement learning. We developed a computer model of the biochemical reaction pathways involved in the phosphorylation of DARPP-32 on Thr34 and Thr75. Ordinary differential equations describing the biochemical reactions were implemented in a single compartment model using the software XPPAUT. Reaction rate constants were obtained from the biochemical literature. The first set of simulations using sustained elevations of dopamine and calcium produced phosphorylation levels of DARPP-32 similar to that measured experimentally, thereby validating the model. The second set of simulations, using the validated model, showed that transient dopamine elevations increased the phosphorylation of Thr34 as expected, but transient calcium elevations also increased the phosphorylation of Thr34, contrary to what is believed. When transient calcium and dopamine stimuli were paired, PKA activation and Thr34 phosphorylation increased compared with dopamine alone. This result, which is robust to variation in model parameters, supports reinforcement learning theories in which activity-dependent long-term synaptic plasticity requires paired glutamate and dopamine inputs.

Calcium↗

PubMed2003

Cholesterol, synaptic function and Alzheimer's disease.

We experimentally modeled neuronal cholesterol imbalance by creating an acute biochemical increase in cholesterol turnover in rat hippocampal slices. This kind of experimental set-up impairs the redistribution of cholesterol from one cell to another via lipoprotein transport. While increasing cholesterol removal or immediately afterwards, we evoked and recorded two brain waveforms, paired pulse facilitation (PPF) and long-term potentiation (LTP), which indicate neurotransmission and synaptic plasticity, respectively. We found that the lack of cholesterol supply to neurons impaired both PPF and LTP. From additional immunofluorescent analysis of the slices, we could demonstrate that the cholesterol imbalance also caused neurodegeneration of hippocampal neural cell processes and the appearance of tau protein pathology in the mossy fibers. We also analyzed rats fed a cholesterol diet and discovered that they had increased hippocampal cholesterol biosynthesis and impaired LTP. Cholesterol-fed rats were also characterized by Alzheimer's-like brain amyloid that we did not observe in the model of acute cholesterol imbalance. Our data and research by others suggest that biological cholesterol homeostasis dysregulation itself plays a key role in synaptic plasticity impairment and neuronal degeneration, and is the primary cause for several Alzheimer's disease hallmarks not limited to brain amyloids. Moreover, changes in the neurochemistry of amyloid beta, tau, neuronal cytoskeleton, and oxidative stress reactions due to Alzheimer's likely represent physiological transitory mechanisms that aim to compensate impaired brain cholesterol dynamics and/or associated neurotransmission and synaptic plasticity failure. Part of this article was published as netprint and is available under the URL http://clinmed.netprints.org/cgi/content/full/2001100005v1.

Acetates↗

PubMed1997

Reinforcement learning by Hebbian synapses with adaptive thresholds.

A central problem in learning theory is how the vertebrate brain processes reinforcing stimuli in order to master complex sensorimotor tasks. This problem belongs to the domain of supervised learning, in which errors in the response of a neural network serve as the basis for modification of synaptic connectivity in the network and thereby train it on a computational task. The model presented here shows how a reinforcing feedback can modify synapses in a neuronal network according to the principles of Hebbian learning. The reinforcing feedback steers synapses towards long-term potentiation or depression by critically influencing the rise in postsynaptic calcium, in accordance with findings on synaptic plasticity in mammalian brain. An important feature of the model is the dependence of modification thresholds on the previous history of reinforcing feedback processed by the network. The learning algorithm trained networks successfully on a task in which a population vector in the motor output was required to match a sensory stimulus vector presented shortly before. In another task, networks were trained to compute coordinate transformations by combining different visual inputs. The model continued to behave well when simplified units were replaced by single-compartment neurons equipped with several conductances and operating in continuous time. This novel form of reinforcement learning incorporates essential properties of Hebbian synaptic plasticity and thereby shows that supervised learning can be accomplished by a learning rule similar to those used in physiologically plausible models of unsupervised learning. The model can be crudely correlated to the anatomy and electrophysiology of the amygdala, prefrontal and cingulate cortex and has predictive implications for further experiments on synaptic plasticity and learning processes mediated by these areas.

Adaptation, Physiological↗

PubMedDate not supplied

The ryanodine receptors Ca2+ release channels: cellular redox sensors?

The release of Ca2+ from intracellular stores mediated by ryanodine receptors (RyR) Ca2+ release channels is essential for striated muscle contraction and contributes to diverse neuronal functions including synaptic plasticity. Through Ca2+-induced Ca2+-release, RyR can amplify and propagate Ca2+ signals initially generated by Ca2+ entry into cardiac muscle cells or neurons. In contrast, RyR activation in skeletal muscle is under membrane potential control and does not require Ca2+ entry. Non-physiological or endogenous redox molecules can change RyR function via modification of a few RyR cysteine residues. This critical review will address the functional effects of RyR redox modification on Ca2+ release in skeletal muscle and cardiac muscle as well as in the activation of signaling cascades and transcriptional regulators required for synaptic plasticity in neurons. Specifically, the effects of endogenous redox-active agents, which induce S-nitrosylation or S-glutathionylation of particular channel cysteine residues, on the properties of muscle RyRs will be discussed. The effects of endogenous redox RyR modifications on cardiac preconditioning will be analyzed as well. In the hippocampus, sequential activation of ERKs and CREB is a requisite for Ca2+-dependent gene expression associated with long lasting synaptic plasticity. Results showing that reactive oxygen/nitrogen species modify RyR channels from neurons and the RyR-mediated sequential activation of neuronal ERKs and CREB produced by hydrogen peroxide and other stimuli will be also discussed.

Animals↗

PubMed1997

Effect of chronic administration of NMDA antagonists on synaptic development.

The current research assessed the role of the N-methyl-D-aspartate (NMDA) receptor in developmental synaptic plasticity. This was accomplished by quantitative analysis of synaptic number and morphology following pharmacological manipulation of NMDA receptor activity using either the competitive antagonist 2-amino-5-phosphonovaleric acid (APV) or the noncompetitive antagonist phencyclidine (PCP). In the first group, 15-day-old male Long-Evans rats were implanted with osmotic minipumps, which administered 50 mM APV or vehicle at a rate of 0.5 microliter per h into the subjects' occipital cortex for 14 days. At age 30 days (P30), the rats were sacrificed and their occipital neocortices were examined. A second group of rats was given subcutaneous injections of 10 mg/kg PCP or vehicle once daily beginning on P5 for a period of 15 days, and was sacrificed on P20. To determine the effects following withdrawal from long-term NMDA antagonism, a third group of animals was given the same PCP injection routine until P20, but was sacrificed on P21, P26, P36, and P56. Developmental administration of APV was associated with a decreased molecular layer depth and estimated total number of synapses. Similarly, PCP induced a reduction in brain weight, molecular layer depth, and estimated total number of synapses. Withdrawal from NMDA antagonism was initially associated with similar results, i.e., reduced brain weight, cortex depth, synaptic density, and estimated total number of synapses, along with an increase in synaptic length. By P36, however, there was a transitory rebound associated with increased molecular layer depth and estimated total number of synapses. These results support the suggestion that NMDA receptor activation is integral to naturally occurring developmental synaptogenesis, and underscore the importance of NMDA receptor involvement in the process of synaptic plasticity.

2-Amino-5-phosphonovalerate↗

PubMed2001

Think globally, translate locally: what mitotic spindles and neuronal synapses have in common.

Early metazoan development is programmed by maternal mRNAs inherited by the egg at the time of fertilization. These mRNAs are not translated en masse at any one time or at any one place, but instead their expression is regulated both temporally and spatially. Recent evidence has shown that one maternal mRNA, cyclin B1, is concentrated on mitotic spindles in the early Xenopus embryo, where its translation is controlled by CPEB (cytoplasmic polyadenylation element binding protein), a sequence-specific RNA binding protein. Disruption of the spindle-associated translation of this mRNA results in a morphologically abnormal mitotic apparatus and inhibited cell division. Mammalian neurons, particularly in the synapto-dendritic compartment, also contain localized mRNAs such as that encoding alpha-CaMKII. Here, synaptic activation drives local translation, an event that is involved in synaptic plasticity and possibly long-term memory storage. Synaptic translation of alpha-CaMKII mRNA also appears to be controlled by CPEB, which is enriched in the postsynaptic density. Therefore, CPEB-controlled local translation may influence such seemingly disparate processes as the cell cycle and synaptic plasticity.

Animals↗

PubMed2003

Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1.

Mammalian target of rapamycin (mTOR) is a key regulator of translational capacity. The mTOR inhibitor rapamycin can prevent forms of protein synthesis-dependent synaptic plasticity such as long-term facilitation in Aplysia and late-phase long-term potentiation (L-LTP) in the hippocampal CA1 region of rodents. In the latter model, two issues remain to be addressed: defining the L-LTP phase sensitive to rapamycin and identifying the site of rapamycin-sensitive protein synthesis. Here, we show that L-LTP is sensitive to application of rapamycin only during the induction paradigm, whereas rapamycin application after the establishment of L-LTP was ineffective. Second, we observed that Thr-389-phosphorylated p70 S6 kinase (p70S6K), the main active phosphoform of the mTOR effector p70S6K, was induced in an N-methyl-D-aspartate and phosphatidylinositol 3-kinase-dependent manner throughout the dendrites but not in the cell bodies of CA1 neurons in hippocampal slices after L-LTP induction. A similar dendrite-wide activation of p70S6K was induced in primary hippocampal neurons by depolarization with KCL or glutamate. In primary hippocampal neurons, the sites of dendritic activation of p70S6K appeared as discrete compartments along dendritic shafts like the hotspots for fast dendritic translation. Conversely, only a subset of dendritic spines also displayed activated p70S6K. Taken together, the present data suggest that the N-methyl-d-aspartate-, phosphatidylinositol 3-kinase-dependent dendritic activation of the mTOR-p70S6K pathway is necessary for the induction phase of protein synthesis-dependent synaptic plasticity. Newly synthesized proteins in dendritic shafts could be targeted selectively to activity-tagged synapses. Thus, coordinated activation of dendrite-wide translation and synaptic-specific activation is likely to be necessary for long-term synaptic plasticity.

Animals↗

PubMed2006

Dendritic mRNAs encode diversified functionalities in hippocampal pyramidal neurons.

BACKGROUND: Targeted transport of messenger RNA and local protein synthesis near the synapse are important for synaptic plasticity. In order to gain an overview of the composition of the dendritic mRNA pool, we dissected out stratum radiatum (dendritic lamina) from rat hippocampal CA1 region and compared its mRNA content with that of stratum pyramidale (cell body layer) using a set of cDNA microarrays. RNAs that have over-representation in the dendritic fraction were annotated and sorted into function groups. RESULTS: We have identified 154 dendritic mRNA candidates, which can be arranged into the categories of receptors and channels, signaling molecules, cytoskeleton and adhesion molecules, and factors that are involved in membrane trafficking, in protein synthesis, in posttranslational protein modification, and in protein degradation. Previously known dendritic mRNAs such as MAP2, calmodulin, and G protein gamma subunit were identified from our screening, as were mRNAs that encode proteins known to be important for synaptic plasticity and memory, such as spinophilin, Pumilio, eEF1A, and MHC class I molecules. Furthermore, mRNAs coding for ribosomal proteins were also found in dendrites. CONCLUSION: Our results suggest that neurons transport a variety of mRNAs to dendrites, not only those directly involved in modulating synaptic plasticity, but also others that play more common roles in cellular metabolism.

Animals↗

PubMed1993

Modified hippocampal long-term potentiation in PKC gamma-mutant mice.

Calcium-phospholipid-dependent protein kinase (PKC) has long been suggested to play an important role in modulating synaptic efficacy. We have created a strain of mice that lacks the gamma subtype of PKC to evaluate the significance of this brain-specific PKC isozyme in synaptic plasticity. Mutant mice are viable, develop normally, and have synaptic transmission that is indistinguishable from wild-type mice. Long-term potentiation (LTP), however, is greatly diminished in mutant animals, while two other forms of synaptic plasticity, long-term depression and paired-pulse facilitation, are normal. Surprisingly, when tetanus to evoke LTP was preceded by a low frequency stimulation, mutant animals displayed apparently normal LTP. We propose that PKC gamma is not part of the molecular machinery that produces LTP but is a key regulatory component.

Animals↗

PubMed2003

Astrocytes and brain function: implications for reproduction.

Recent evidence suggests that astrocytes have important neuroregulatory functions in addition to their classic functions of support and segregation of neurons. These newly revealed functions include regulation of neuron communication, neurosecretion, and synaptic plasticity. Although these actions occur throughout the brain, this review will focus on astrocyte-neuron interactions in the hypothalamus, particularly with respect to their potential contribution to the regulation of gonadotropin-releasing hormone (GnRH) secretion and reproduction. Hypothalamic astrocytes have been documented to release a variety of neuroactive factors, including transforming growth factors-alpha and -beta, insulin-like growth factor-1, prostaglandin E2, and the neurosteroid, 3 alpha-hydroxy-5 alpha-pregnane-20-one. Each of these factors has been shown to stimulate GnRH release, and receptors for each factor have been documented on GnRH neurons. Astrocytes have also been implicated in the regulation of synaptic plasticity in key areas of the hypothalamus that control GnRH release, an effect achieved by extension and retraction of glial processes (i.e., glial ensheathment). Through this mechanism, the number of synapses on GnRH neurons and GnRH regulatory neurons can potentially be modulated, thereby influencing the activation state of GnRH neurons. The steroid hormone 17beta-estradiol, which triggers the GnRH and luteinizing hormone surge, has been shown to induce the astrocyte-regulated changes in hypothalamic synaptic plasticity, as well as enhance formation and release of the astrocyte neuroactive factors, thereby providing another potential mechanistic layer for astrocyte regulation of GnRH release. As a whole, these studies provide new insights into the diversity of astrocytes and their potential role in reproductive neuroendocrine function.

Animals↗

PubMed1999

The effects of chronic lead exposure on long-term depression in area CA1 and dentate gyrus of rat hippocampus in vitro.

Long-term potentiation (LTP) and long-term depression (LTD), two forms of synaptic plasticity, are believed to underlie the mechanisms of learning and memory. Previous studies have demonstrated that low-level lead exposure can impair the induction and maintenance of LTP in vivo and in vitro. The present study was carried out to investigate whether the low-level lead exposure affected the induction and maintenance of LTD. Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams drinking 0.2% lead acetate solution. Field excitatory postsynaptic potentials (EPSPs) were recorded in hippocampal slices in adult rats (50-65 days) to study the alterations of LTD in area CA1 and dentate gyrus (DG) of hippocampus following chronic lead exposure. The input-output (I/O) curves before conditioning in both areas showed no evident alterations in basic synaptic transmission between the control and lead exposure groups. In area CA1, the mean amplitude of EPSP slope in control rats (61+/-11%, n=15) decreased significantly greater than that in lead-exposed rats (78+/-8%, n=8, P<0.05) following low frequency stimulation (LFS, 1 Hz, 15 min), which lasted at least 45 min. In area DG, with application of the same LFS, the LTD was induced in control rats (72+/-22%, n=8), while the LFS failed to induce LTD in lead-exposed rats (100+/-26%, n=8). These results showed that chronic lead exposure affected the induction of LTD in both area CA1 and DG. The effect of lead on synaptic plasticity in area CA1 was also investigated. The alteration of the amplitude of LTP in hippocampal slices caused by lead was reexamined in order to compare with that on LTD (control: 189+/-23, n=5; lead-exposed: 122+/-12, n=10). The result demonstrated that low-level lead exposure could reduce the range of synaptic plasticity, which might underlie the dysfunction of learning and memory caused by chronic lead exposure.

Animals↗

PubMed2004

Tracing functional circuits using c-Fos regulated expression of marker genes targeted to neuronal projections.

We have developed novel techniques to trace functionally activated circuits and synaptic plasticity within the brain. We have generated transgenic mice, FTL, which contain a tau-lacZ fusion gene regulated by the promoter for c-fos. Following a particular nervous system stimulation in these mice, only neurons, which are functionally activated, will express LacZ, which is targeted to neuronal processes by the tau protein. In the FTL mice, we found highly inducible expression of lacZ by a range of different stimuli, and successful targeting of expression to neuronal cell bodies, axons and dendrites. To test if a functionally activated circuit could be visualized, the mice were deprived of water, which activates nuclei involved in body fluid homeostasis. LacZ was induced in these nuclei and their projections, allowing the mapping of a neuroendocrine circuit. Further studies have employed these mice in the analysis of neurons and circuits activated in vision, and learning and memory. We have also developed methods to measure markers of synaptic plasticity in the brain, and found significant experience dependent changes in the levels of these markers in different parts of the brain. We believe these techniques will aid in the identification of circuits for many different brain functions, and within those circuits, the locations of synaptic plasticity.

Animals↗

PubMed1995

Mechanism for modulation of nicotinic acetylcholine receptors that can influence synaptic transmission.

Only recently has it been appreciated that neuronal nicotinic ACh receptors (NnAChRs) are highly permeable to Ca2+ and are modulated by Ca2+ in a dose-dependent manner. These findings suggest that Ca2+ could have roles in cholinergic synaptic plasticity. We report a possible mechanism for Ca(2+)-initiated synaptic plasticity that differs from the intracellular Ca2+ cascade associated with plasticity of glutamatergic synapses. Rapid changes in external Ca2+ modulate cholinergic spontaneous synaptic currents in superior cervical ganglionic sympathetic neurons. Inhibition of cholinergic currents by chlorisondamine, which blocks only open channels and becomes trapped in the pore, showed that the modulation is not by a mechanism that activates a previously unresponsive population of NnAChRs. Rather, single-channel recordings with ganglionic NnAChRs from chromaffin cells indicated that Ca2+ directly alters the probability of the channels being open. We hypothesize from the results that activity-dependent decreases in external Ca2+, which occur throughout the nervous system, could directly underlie a rapid negative-feedback mechanism that decreases the responsiveness of NnAChRs at synapses. When external Ca2+ is decreased, presynaptic Ca2+ currents and transmitter release also are diminished. Thus, several mechanisms could combine to potently and rapidly depress synaptic nicotinic receptors until the external Ca2+ concentration recovers.

Animals↗

PubMed2005

Synaptic fatigue at the naive perforant path-dentate granule cell synapse in the rat.

Synaptic activation at low frequency is often used to probe synaptic function and synaptic plasticity, but little is known about how such low-frequency activation itself affects synaptic transmission. In the present study, we have examined how the perforant path-dentate granule cell (PP-GC) synapse adapts to low-frequency activation from a previously non-activated (naive) state. Stimulation at 0.2 Hz in acute slices from developing rats (7-12 days old) caused a gradual depression of the AMPA EPSC (at -80 mV) to about half within 50 stimuli. This synaptic fatigue was unaffected by the NMDA and metabotropic glutamate (mGlu) receptor antagonists d-AP5 and LY-341495. A smaller component of this synaptic fatigue was readily reversible when switching to very low-frequency stimulation (0.033-0.017 Hz) and is attributed to a reversible decrease in release probability, which is probably due to depletion of readily releasable vesicles. Thus, it was expressed to the same extent by AMPA and NMDA EPSCs, and was associated with a decrease in quantal content (measured as 1/CV(2)) with no change in the paired-pulse ratio. The larger component of the synaptic fatigue was not readily reversible, was selective for AMPA EPSCs and was associated with a decrease in 1/CV(2), thus probably representing silencing of AMPA signalling in a subset of synapses. In adult rats (> 30 days old), the AMPA silencing had disappeared while the low-frequency depression remained unaltered. The present study has thus identified two forms of synaptic plasticity that contribute to fatigue of synaptic transmission at low frequencies at the developing PP-GC synapse; AMPA silencing and a low-frequency depression of release probability.

Animals↗

PubMed2006

Long-term depression of kainate receptor-mediated synaptic transmission.

Kainate receptors (KARs) have been shown to be involved in hippocampal mossy fiber long-term potentiation (LTP); however, it is not known if KARs are involved in the induction or expression of long-term depression (LTD), the other major form of long-term synaptic plasticity. Here we describe LTD of KAR-mediated synaptic transmission (EPSC(KA) LTD) in perirhinal cortex layer II/III neurons that is distinct from LTD of AMPAR-mediated transmission, which also coexists at the same synapses. Induction of EPSC(KA) LTD requires a rise in postsynaptic Ca(2+) but is independent of NMDARs or T-type voltage-gated Ca(2+) channels; however, it requires synaptic activation of inwardly rectifying KARs and release of Ca(2+) from stores. The synaptic KARs are regulated by tonically activated mGluR5, and expression of EPSC(KA) LTD occurs via a mechanism involving mGluR5, PKC, and PICK1 PDZ domain interactions. Thus, we describe the induction and expression mechanism of a form of synaptic plasticity, EPSC(KA) LTD.

Animals↗

PubMed2006

The extracellular signal-regulated kinase pathway: an emerging promising target for mood stabilizers.

PURPOSE OF REVIEW: There exists a growing appreciation that, though not classical neurodegenerative disorders, severe mood disorders are associated with regional impairments of structural plasticity and cellular resilience. Exciting recent data suggest that synaptic plasticity probably is involved in mechanisms of actions of mood stabilizers and antidepressants. Notably, the extracellular signal-regulated kinase pathway is a critical 'plasticity pathway' in the brain. The present review summarizes neurobiological, pharmacological, and behavioral data on the role of the extracellular signal-regulated kinase pathway in regulating some of the symptoms of bipolar disorder and as a therapeutically relevant target for mood stabilizers. RECENT FINDINGS: The extracellular signal-regulated kinase pathway is known to mediate neurotrophic actions and synaptic plasticity. Treatment with lithium and valproate activates the extracellular signal-regulated kinase pathway in cultured cells and in prefrontal cortex and hippocampus. In addition, lithium or valproate treatment promotes neurogenesis, neurite growth, and cell survival. The extracellular signal-regulated kinase pathway is also targeted by antipsychotics. Modulation of the central nervous system extracellular signal-regulated kinase pathway induces animal behavioral alterations reminiscent of manic symptoms; these complex behaviors probably depend on the effects of extracellular signal-regulated kinase on discrete brain regions and the presence of other interacting molecules. SUMMARY: The extracellular signal-regulated kinase pathway may represent a novel target for the development of improved therapeutics for bipolar disorder.

Animals↗