Regulation Of Neuronal Plasticity Research Articles

Paliperidone as a mood stabilizer: A pre-frontal cortex synaptoneurosomal proteomics comparison with lithium and valproic acid after chronic treatment reveals similarities in protein expression

A series of recent studies has demonstrated that the molecules involved in regulation of neuronal plasticity are also involved in the mode of action of antidepressants and mood stabilizer drugs. Intracellular calcium signaling, energy metabolism, and neuronal plasticity can be influenced by inducing axonal remodeling and increasing levels of certain synaptic proteins. Because antipsychotic drugs are used as mood stabilizers our studies focused on a newly-marketed antipsychotic drug, paliperidone. We determined changes in rat synaptoneurosomal proteins after chronic treatment with paliperidone, lithium salt, or valproic acid in order to find similarities or differences between the mode of action of paliperidone and these two classical mood stabilizers. We determined differential protein expression profiles in prefrontal cortex (PFC) of male Sprague–Dawley rats ( n = 4/group). Synaptoneurosomal-enriched preparations were obtained from PFC after chronic treatment with these three drugs. Proteins were separated by 2D-DIGE and identified by nano-LC-MS/MS. We observed similar protein expression profiles at the synaptoneurosomal level, suggesting that the mode of action for paliperidone is similar to that of lithium and valproic acid. However, the expression profile for paliperidone was more similar to that of lithium. Pathways affected in common by these two drugs included oxidative phosphorylation, electron transport, carbohydrate metabolism, and post-synaptic cytokinesis implicating the effects of these drugs in signaling pathways, energy metabolism, and synaptic plasticity.

Curcumin Stimulates Proliferation of Embryonic Neural Progenitor Cells and Neurogenesis in the Adult Hippocampus

Curcumin is a natural phenolic component of yellow curry spice, which is used in some cultures for the treatment of diseases associated with oxidative stress and inflammation. Curcumin has been reported to be capable of preventing the death of neurons in animal models of neurodegenerative disorders, but its possible effects on developmental and adult neuroplasticity are unknown. In the present study, we investigated the effects of curcumin on mouse multi-potent neural progenitor cells (NPC) and adult hippocampal neurogenesis. Curcumin exerted biphasic effects on cultured NPC; low concentrations stimulated cell proliferation, whereas high concentrations were cytotoxic. Curcumin activated extracellular signal-regulated kinases (ERKs) and p38 kinases, cellular signal transduction pathways known to be involved in the regulation of neuronal plasticity and stress responses. Inhibitors of ERKs and p38 kinases effectively blocked the mitogenic effect of curcumin in NPC. Administration of curcumin to adult mice resulted in a significant increase in the number of newly generated cells in the dentate gyrus of hippocampus, indicating that curcumin enhances adult hippocampal neurogenesis. Our findings suggest that curcumin can stimulate developmental and adult hippocampal neurogenesis, and a biological activity that may enhance neural plasticity and repair.

Acute stress regulation of neuroplasticity genes in mouse hippocampus CA3 area — Possible novel signalling pathways

Stress exposure can lead to the precipitation of psychiatric disorders in susceptible individuals, but the molecular underpinnings are incompletely understood. We used forced swimming in mice to reveal stress-regulated genes in the CA3 area of the hippocampus. To determine changes in the transcriptional profile 4 h and 8 h after stress exposure microarrays were used in the two mouse strains C57BL/6J and DBA/2J, which are known for their differential stress response. We discovered a surprisingly distinct set of regulated genes for each strain and followed selected ones by in situ hybridisation. Our results support the concept of a phased transcriptional reaction to stress. Moreover, we suggest novel stress-elicited pathways, which comprise a number of genes involved in the regulation of neuronal plasticity. Furthermore, we focused in particular on dihydropyrimidinase like 2, to which we provide evidence for its regulation by NeuroD, an important factor for neuronal activity-dependent dendritic morphogenesis.

Adaptive immunity affects learning behavior in mice

Regulation of neuronal plasticity by the immune system is an evolving field of modern neuroscience. Here we employ immune deficient mice to examine the role of the immune system in learning behavior of mice in a variety of cognitive tasks. While no motivation or motor function deficits are evident in severe combined immune deficient (scid) mice, there was significant impairment in acquisition of cognitive tasks as compared to wild-type (WT) control mice. Moreover, acute depletion of adaptive immunity in adult WT mice significantly impaired learning behavior. Passive transfer of autologous T cells into WT mice following ablation of adaptive immunity restored previously impaired cognitive function. These results suggest that throughout lifetime, immune system supports cognitive function and may therefore have far-reaching therapeutic implications for cognitive disorders.

TDP‐43, the signature protein of FTLD‐U, is a neuronal activity‐responsive factor

TDP-43, recently identified as a signature protein of the pathogenic inclusions in the brains cells of frontotemporal lobar degeneration patients, is a 43 kDa RNA-binding protein. It has been known mainly as a nuclear factor capable of repressing transcription and promoting exon exclusion. TDP-43 also forms distinct nuclear substructures linking different types of nuclear bodies. In this study, we provide the first evidence supporting TDP-43 as a neuronal activity-responsive factor in the dendrites of hippocampal neurons. In particular, TDP-43 resides in the somatodendrites mainly in the form of RNA granules colocalized with the post-synaptic protein PSD-95. These granules also contain RNAs including at least the beta-actin mRNA and CaMKIIalpha mRNA. Furthermore, TDP-43 is localized in the dendritic processing (P) body and it behaves as a translational repressor in an in vitro assay. Related to this, repetitive stimuli by KCl greatly enhance the colocalization of TDP-43 granules with FMRP and Staufen 1, two RNA-binding proteins known to regulate mRNA transport and local translation in neurons. These data together suggest that TDP-43 is a neuronal activity-responsive factor functioning in the regulation of neuronal plasticity, the impairment of which would lead to the development of certain forms of neurodegenerative diseases including frontotemporal lobar degeneration.

The Kv4.2 mediates excitatory activity‐dependent regulation of neuronal excitability in rat cortical neurons

Neuronal excitability can cooperate with synaptic transmission to control the information storage. This regulation of neuronal plasticity can be affected by alterations in neuronal inputs and accomplished by modulation of voltage-dependent ion channels. In this study, we report that enhanced excitatory input negatively regulated neuronal excitability. Enhanced excitatory input by glutamate, electric field stimulation or high K+ increased transient outward K+ current, whereas did not affect the delayed rectifier K+ current in rat cultured cortical neurons. Both the voltage-dependent K+ channel 4.2 and 4.3 subunits contributed to the increase. The increase in the K+ current density by Kv4.2 was ascribed to its cytoplasmic membrane translocation, which was mediated by NMDA type of glutamate receptor. Furthermore, enhanced excitatory input inhibited neuronal excitability. Taken together, our results suggest that excitatory neurotransmission affects neuronal excitability via the regulation of the K+ channel membrane translocation.

Evaluation of the role of Disabled-2 in nerve growth factor-mediated neurite outgrowth and cellular signalling

Disabled-2 (DAB2) is an adapter protein that plays a key role in cell proliferation and differentiation. We reported here that DAB2 is expressed in various regions of rat central nervous system and is most abundant in the olfactory bulb. The up-regulation of DAB2 upon 5,7-dihydroxytryptamine-induced spinal cord lesion implicates that DAB2 may participate in the regulation of neuronal plasticity. To investigate DAB2 function in the regulation of neurite outgrowth, the rat p59 and p82 form of DAB2 was individually and stably expressed in the PC12 cells. Both p59 and p82 inhibited nerve growth factor (NGF)-induced neurite outgrowth concomitantly with a decrease in the expression of neuron-specific cytoskeleton protein β-tubulin III. To unveil the molecular mechanism of DAB2 in NGF signaling, we found that RhoA-GTPase activity was up-regulated in DAB2 stable lines whereas the Ras/MAPK and PI3-kinase/Akt signaling was not affected. The inhibitory effect of DAB2 on NGF-mediated neurite outgrowth was reversed by the pretreatment of Rho-kinase (ROCK) inhibitor Y27632, implicating that DAB2 modulates RhoA/ROCK signaling. Together, this study defines a role of DAB2 in the control of neuronal plasticity and demonstrates for the first time that DAB2 is a negative regulator in NGF-mediated neurite outgrowth.

Diazepam-induced adaptive plasticity revealed by alpha1 GABAA receptor-specific expression profiling.

Benzodiazepines are in wide clinical use for their sedative and tranquilizing actions, the former being mediated via alpha1-containing GABAA receptors. The signal transduction pathways elicited beyond the receptor are only poorly understood. Changes of transcript levels in cerebral cortex induced by acute diazepam administration were therefore compared by microarray analysis between wild-type and point mutated alpha1(H101R) mice, in which the alpha1 GABAA receptor subunit had been rendered insensitive to diazepam. In wild-type animals, diazepam reduced the expression levels of the alpha subunit of the calcium/calmodulin-dependent protein kinase II, as well as brain-derived neurotrophic factor, MAP kinase phosphatase, transcription factor GIF, c-fos and nerve growth factor induced gene-A. None of these transcripts was changed in the alpha1(H101R) mice after treatment with diazepam. Thus, the sedative action of diazepam is correlated with a selective down-regulation of transcripts involved in the regulation of neuronal plasticity and neurotrophic responses. Most transcript changes were transient except for the decrease of the CaMKIIalpha transcript which persisted even 40 h after the single dose of diazepam. This long-term alteration is likely to contribute to the resetting of the neuronal responsiveness, which may be involved in rebound phenomena and, under chronic treatment, in the development of tolerance and dependence.

EXPERIENCE-DEPENDENT IMMEDIATE EARLY GENE EXPRESSION IN THE ADULT CENTRAL NERVOUS SYSTEM: EVIDENCE FROM ENRICHED-ENVIRONMENT STUDIES

Here I discuss evidence from our group's work that implicates the immediate early genes NGFI-A and arc as possible regulators of neuronal plasticity. The enriched environment (EE) paradigm has been demonstrated to induce neural plasticity in both developing and mature mammals. Others and we have recently demonstrated that adult rats placed within an enriched environment underwent central nervous system-wide increases in the expression levels for the IEGs NGFI-A and arc. The relationships between the altered expression profiles for both genes in response to an EE exposure, and their putative role in orchestrating network restructuring in response to enhanced environmental complexity are discussed

Levels of protein kinase C and nitric oxide synthase activity in rats exposed to sub chronic low level lead.

The intracellular regulation of protein kinase C (PKC) and nitric oxide synthase (NOS) in relation to the accumulation of lead (Pb2+) in various brain regions following low-level lead exposure (50 ppm) for 90 days in rats was investigated. PKC and NOS are important enzymes in mediating cellular transduction mechanisms and in the regulation of neuronal plasticity. Rats exposed to Pb2+ resulted in blood Pb2+ levels similar to those observed in children affected due to Pb2+ exposure. Further, we examined whether Pb2+ accumulation changed the intracellular signaling mechanisms in different brain regions. Results of these experiments indicate that significant region specific Pb2+ accumulation is associated with down regulation of PKC. The down regulation of PKC increased the activity of NOS following Pb2+ exposure. Thus, the change in PKC activity in respect to Pb2+ accumulation increased NOS activity. These results suggest that neuronal toxicity during Pb2+ exposure is linked to the modulation of PKC followed by NOS activation.

Protein kinase C iota protects neural cells against apoptosis induced by amyloid β-peptide

Protein kinase C (PKC) isoforms are increasingly recognized as playing important roles in the regulation of neuronal plasticity and survival. Recent findings from studies of non-neuronal cells suggest that atypical isoforms of PKC can modulate apoptosis in various paradigms. Because increasing data support a role for neuronal apoptosis in the pathogenesis of Alzheimer’s disease (AD), we tested the hypothesis that PKCiota (PKCι) can modify vulnerability of neural cells to apoptosis induced by amyloid β-peptide (ABP), a cytotoxic peptide linked to neuronal degeneration in AD. Overexpression of PKCι increased the resistance of PC12 cells to apoptosis induced by ABP. Associated with the increased resistance to apoptosis were improved mitochondrial function and reduced activity of caspases. In addition, ABP-induced increases in levels of oxidative stress and intracellular calcium levels were attenuated in cells overexpressing PKCι. These findings suggest that PKCι prevents apoptosis induced by ABP by interrupting the cell death process at a very early step, thereby allowing the cells to maintain ion homeostasis and mitochondrial function.

Regulation of neuronal plasticity in the central nervous system by phosphorylation and dephosphorylation.

Neuronal plasticity can be defined as adaptive changes in structure and function of the nervous system, an obvious example of which is the capacity to remember and learn. Long-term potentiation and long-term depression are the experimental models of memory in the central nervous system (CNS), and have been frequently utilized for the analysis of the molecular mechanisms of memory formation. Extensive studies have demonstrated that various kinases and phosphatases regulate neuronal plasticity by phosphorylating and dephosphorylating proteins essential to the basic processes of adaptive changes in the CNS. These proteins include receptors, ion channels, synaptic vesicle proteins, and nuclear proteins. Multifunctional kinases (cAMP-dependent protein kinase, Ca2+/phospholipid-dependent protein kinase, and Ca2+/calmodulin-dependent protein kinases) and phosphatases (calcineurin, protein phosphatases 1, and 2A) that specifically modulate the phosphorylation status of neuronal-signaling proteins have been shown to be required for neuronal plasticity. In general, kinases are involved in upregulation of the activity of target substrates, and phosphatases downregulate them. Although this rule is applicable in most of the cases studied, there are also a number of exceptions. A variety of regulation mechanisms via phosphorylation and dephosphorylation mediated by multiple kinases and phosphatases are discussed.

Interactions with males promote rapid changes in gonadotropin-releasing hormone immunoreactive cells.

It is well known that hormones can regulate behaviors. However, the reciprocal interaction, the effects of behavior on hormones, has received less direct experimental attention. Dramatic changes in hormones and behaviors occur at puberty and some of these changes can be triggered by modification of the social environment. Interactions with males accelerate production of pulsatile release of gonadotropins and steroid hormones which, in turn, initiate estrous cycles, ovulation, and sexual behavior in females. Ultimately all of these actions are controlled by changes in production and secretion of gonadotropin-releasing hormone (GnRH). Little is known about how behavior affects GnRH-producing neurons. In female musk shrews, the first mating initiates the onset of puberty. Musk shrews lack a behavioral estrous cycle and they become receptive within minutes after their first contact with a male. As soon as 1 h after interactions with males there is a significant increase in the numbers of GnRH-immunoreactive (GnRH-ir) neurons in specific brain regions. In the present study, we examined changes in GnRH-ir cell number during the initial mating bout. We found dynamic changes in the numbers of GnRH-containing cells, correlated with changes in behavior. Interactions with males for less than 30 minutes induced a significant increase in GnRH-ir neurons in specific olfactory-related forebrain nuclei. At the end of a mating bout, numbers of GnRH-ir neurons declined. Because behavioral interactions have rapid and pronounced effects on the neurons that produce GnRH, this model can be used to examine the behavioral regulation of neuronal plasticity.

Neuronal Ca2+/calmodulin-dependent protein kinases.

Widespread localization, responsiveness to numerous signal transduction systems, and broad substrate specificity enable the multifunctional CaM kinase to mediate regulation of many cellular functions. The abundance and diversity of CaM kinase substrates attest to its role as a multifunctional kinase. However, expanded identification of its in situ substrates as well as the consequences of their regulation by phosphorylation needs to be accomplished. Recently identified substrates have contributed to the list of potential functions for the CaM kinase. CREB is a hormonally stimulated transcriptional activator, and CaM kinase may lie on the pathway to its activation. This pathway could provide an interface between the potentiation of Ca2+ signals by CaM kinase and longer-term modifications of neuronal gene expression. The ryanodine receptor, as well as phospholamban, are involved in cardiac Ca2+ homeostasis, and their regulation by CaM kinase phosphorylation suggests the possibility of some feedback control of intracellular Ca2+ levels by CaM kinase. Regulation of neuronal plasticity by phosphorylation of synapsin I and of postsynaptic substrates necessary for long-term potentiation is another dynamic area of investigation. The study of substrates and their functions promises to continue providing exciting insights into the control of cellular signalling by Ca2+. Molecular cloning has enabled structural comparison of neuronal isoforms of the kinase, and has revealed the existence of closely related subunits. Subunits identified to data differ substantially only in two small variable domains, yet their expression in various tissues and during the course of development is precisely controlled. What unique properties do these small variable domains impart to the different isoforms? What directs high concentrations of kinase to a particular subcellular localization, and especially to the PSD? Further molecular cloning will undoubtedly determine whether other multifunctional CaM kinases with unique structures and properties exist. Finally, studies on the autoregulatory properties of CaM kinase have provided a fascinating picture of how this molecule can alone encode responses to Ca2+ signals, potentiating both the duration and magnitude of its activity. Autophosphorylation of the Thr286 autonomy site both traps calmodulin and permits Ca(2+)-independent activity after calmodulin dissociates. Further analysis of the role of the holoenzyme structure in these modulations will help clarify remaining mechanistic questions. Studies performed during the past few years have clearly established that this Ca(2+)-independent activity is generated in situ in response to a variety of cell stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

Metabotropic glutamate receptors and neuronal toxicity.

Specific glutamate receptors coupled to polyphosphoinositide (PPI) hydrolysis have been described in brain slices, cultured neurons, and astrocytes, and in amphibian oocytes injected with rat brain mRNA (Sladeczek et al., 1985; Nicoletti et al., 1986a,b; Sugiyama et al., 1987). In most of the systems, metabotropic receptors are activated by lS,3R-aminocyclopentandicarboxylic acid (ACPD), quisqualate, ibotenate, and L-glutamate, but not by α-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA) (Nicoletti et al., 1986a; Schoepp and Johnson, 1988; 1989; Palmer et al., 1989). Trans-ACPD has been described as the most selective agonist of metabotropic receptors (Palmer et al., 1989), although it is less potent than quisqualate in stimulating inositolphosphate formation. In brain slices, stimulation of PPI hydrolysis by metabotropic receptor agonists is extremely high at the earlier stages of postnatal development (within the first 2 weeks after birth) and progressively declines during maturation (Nicoletti et al., 1986a). In adult tissue, the activation of metabotropic receptors is amplified in response to deafferentation (Nicoletti et al., 1987), as well as after induction of long-term potentiation (Aronica et al., 1991) or electrical kindling (Iadarola et al, 1986; Akiyama et al., 1987). Hence, it is likely that metabotropic receptors contribute to the synaptic events involved in the regulation of neuronal plasticity. However, based on the toxic effects of quisqualate in hippocampal slices (Garthwaite and Garthwaite, 1989) and cultured cortical neurons (Patel et al., 1990), a role for metabotropic receptors in the mechanism of neuronal degeneration has been suggested. We have addressed this problem in primary cultures of cerebellar neurons.

Molecular mechanisms of neuronal plasticity during learning: The role of secondary messengers

We present published data along with our own results concerning the role of second messengers and their intracellular receptors in molecular mechanisms associated with the plasticity of neurons during learning. The participation of cyclic 3',5'-adenosine monophosphate, cyclic 3',5'-guanosine monophosphate, calcium, calmodulin, and also the metabolic products of inositol phospholipids, inositol-1,4,5-triphosphate, diacylglycerol and the protein kinase C activated by it, arachidonic acid, and the products of its lipoxygenase oxidation during the regulation of neuronal plasticity over the course of prolonged potentiation, sensitization, habituation, and classical associative training are discussed.