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Results for “Neuronal Plasticity”

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PubMed2003

Selective regulation of neurite extension and synapse formation by the beta but not the alpha isoform of CaMKII.

Neurite extension and branching are important neuronal plasticity mechanisms that can lead to the addition of synaptic contacts in developing neurons and changes in the number of synapses in mature neurons. Here we show that Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates movement, extension, and branching of filopodia and fine dendrites as well as the number of synapses in hippocampal neurons. Only CaMKIIbeta, which peaks in expression early in development, but not CaMKIIalpha, has this morphogenic activity. A small insert in CaMKIIbeta, which is absent in CaMKIIalpha, confers regulated F-actin localization to the enzyme and enables selective upregulation of dendritic motility. These results show that the two main neuronal CaMKII isoforms have markedly different roles in neuronal plasticity, with CaMKIIalpha regulating synaptic strength and CaMKIIbeta controlling the dendritic morphology and number of synapses.

Actins↗

PubMed2000

Effects of A1 and A2 adenosine receptor antagonists on the induction and reversal of long-term potentiation in guinea pig hippocampal slices of CA1 neurons.

1. Using simultaneous recordings of the field EPSP and the population spike in the CA1 neurons of guinea pig hippocampal slices, we confirmed that delivery of a high-frequency stimulation (tetanus: 100 pulses at 100 Hz) produced robust long-term potentiation of synaptic efficacy (LTP) in two independent components, a synaptic component that increases field excitatory postsynaptic potentials (EPSPs) and a component that results in a larger population spike amplitude for a given EPSP size (E-S potentiation). 2. In the same cells, reversal of LTP (depotentiation; DP) in the field EPSP and in the E-S component is achieved by delivering low-frequency afferent stimulation (LFS: 1 Hz, 1000 pulses) 20 min after the tetanus. 3. When the tetanus or LFS was applied to CA1 inputs in the presence of an adenosine A1 receptor antagonist, 8-cyclopentyltheophylline (1 microM), the field EPSP was enhances in LTP and attenuated in DP, while the E-S relationship was not significantly affected in either LTP or DP. 4. When similar experiments were performed using an A2 receptor antagonist, CP-66713 (10 microM), the field EPSP was blocked in LTP but facilitated in DP, while E-S potentiation was enhanced during both LTP and DP. 5. The results show that endogenous adenosine, acting via A1 or A2 receptors, modulates both the synaptic and the E-S components of the induction and reversal of LTP. Based on the results, we discuss the key issue of the contribution of these receptors to the dynamics of neuronal plasticity modification in hippocampal CA1 neurons.

Action Potentials↗

PubMed1999

Effects of adenosine receptors on the synaptic and EPSP-spike components of long-term potentiation and depotentiation in the guinea-pig hippocampus.

1. Long-term potentiation (LTP) of synaptic efficacy comprises two components: a synaptic component consisting of increased field excitatory postsynaptic potentials (EPSPs), and a component consisting of a larger population spike amplitude for a given EPSP size (E-S potentiation). In hippocampal CA1 neurons, delivery of three weak bursts (5 pulses at 100 Hz, 20 min intervals) induced LTP in both the EPSP and E-S components. In the same cells, reversal of LTP (depotentiation, DP) in the field EPSP and the E-S component was achieved by delivering three trains of low-frequency stimuli (LFS; 200 pulses at 1 Hz, 20 min intervals). 2. The effects of adenosine A1 and A2 receptor antagonists on the synaptic and E-S components of LTP and DP in CA1 neurons were studied by perfusing guinea-pig hippocampal slices with either 8-cyclopentyltheophylline (8-CPT) or CP-66713. 3. When bursts or LFS were applied to CA1 inputs in the presence of the A1 receptor antagonist 8-CPT, the field EPSP was enhanced in LTP and attenuated in DP, while the E-S relationship was not significantly affected in either LTP or DP. 4. When similar experiments were performed using the A2 receptor antagonist CP-66713, the field EPSP was blocked in LTP, but facilitated in DP, while E-S potentiation was enhanced during both LTP and DP. 5. The results show that A1 and A2 adenosine receptors modulate both the synaptic and E-S components of the induction and reversal of LTP. Based on these results, we discuss the key issue of the contribution of these receptors to the dynamics of neuronal plasticity modification in hippocampal CA1 neurons.

Action Potentials↗

PubMed2006

Transcranial magnetic stimulation: the method and application.

Transcranial magnetic stimulation is a noninvasive method for stimulation of brain that is based on the ability of magnetic field to penetrate skull and brain meninges, subsequently inducing electric current in the brain tissues that produces neuronal depolarization and generation of action potentials. Moreover, transcranial magnetic stimulation has effects on neurochemical and synaptic processes in neurons. Due to its easy use and relatively fair side effects, nowadays, transcranial magnetic stimulation is widely used in neurosciences and medicine. The main areas of transcranial magnetic stimulation application are: 1) the investigation of cortical and spinal excitability, 2) the investigation of neuronal plasticity, 3) the investigation of neuronal connectivity, 4) functional mapping, and 5) the treatment of some neurological and psychiatric disorders. Transcranial magnetic stimulation alone or in combination with other noninvasive neuroimaging (PET--positron emission topography, MRI--magnetic resonance imaging) and neurofunctional (EEG--electroencephalography, ERP--event-related potentials, fMRI--functional magnetic resonance imaging) methods allows conducting research on brain functions. Thus, transcranial magnetic stimulation is suitable as a diagnostic tool in neurologic and neuropsychiatric brain research.

Action Potentials↗

PubMed1993

Seizure-like activity disrupts LTP in vitro.

Amnesia is one of the most common consequences of seizures. We modelled this phenomenon in the in vitro hippocampal slice preparation by examining effects of seizure-like activity on long-term potentiation (LTP). LTP is an expression of neuronal plasticity which has been correlated with learning. Electrographic seizures (EGSs) were induced in area CA1 by electrical stimulation of CA3. Trains of tetanic stimuli were then immediately delivered to the Schaffer collateral-CA1 pathway in order to induce LTP. The subsequent LTP in these test slices was significantly lower in magnitude compared to LTP in control slices (with no EGSs). LTP could be successfully induced in test slices 1 h after the EGS. EGSs alone produced no long-lasting effect on baseline responses. These results indicate that the hippocampal slice preparation may serve as a model system in which to study the mechanisms by which seizures can disrupt neuronal plasticity.

Amnesia↗

PubMed1990

Decreased density, but not number, of N-methyl-D-aspartate, glycine and phencyclidine binding sites in hippocampus of senescent rats.

Aging is associated with reduced rates of kindling and spatial learning. Blockade of N-methyl-D-aspartate (NMDA) receptors in young animals produces effects similar to those of aging. These findings raise the possibility that age-dependent reductions in neuronal plasticity are the consequence of decreased NMDA receptor-mediated neurotransmission. Conceivably this reduction could be due to an alteration in the NMDA receptor itself. To test this idea we quantified ligand binding to 3 distinct sites on the NMDA receptor/channel complex in hippocampal membranes prepared from 3- and 24-month-old Fischer-344 rats. The binding parameters of the NMDA, glycine and non-competitive antagonist (A.K.A. phencyclidine) sites on the NMDA receptor/channel complex were examined using [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([3H]CPP), [3H]glycine and [3H]N-(1-[2-thienyl]cyclohexyl)3,4-piperidine ([3H]TCP), respectively. Aging produced no change in the affinity or stoichiometry of the binding sites. Aging was associated with a 30% reduction in the density of each of the 3 binding sites (when expressed as sites/mg membrane protein). However, this reduction in receptor density was the consequence of increased protein content in the hippocampus of aged animals, not a reduction in the number of binding sites. These findings suggest that a selective alteration in the NMDA receptor/channel complex itself does not account for the age-dependent reductions in neuronal plasticity.

Aging↗

PubMed1998

Influence of long-term hyper-gravity on the reactivity of succinic acid dehydrogenase and NADPH-diaphorase in the central nervous system of fish: a histochemical study.

In the course of a densitometric evaluation, the histochemically demonstrated reactivity of succinic acid dehydrogenase (SDH) and of NADPH-diaphorase (NADPHD) was determined in different brain nuclei of two teleost fish (cichlid fish Oreochromis mossambicus, swordtail fish Xiphophorus helleri), which had been kept under 3g hyper-gravity for 8 days. SDH was chosen since it is a rate limiting enzyme of the Krebs cycle and therefore it is regarded as a marker for metabolic and neuronal activity. NADPHD reactivity reflects the activity of nitric oxide synthase. Nitric oxide (NO) is a gaseous intercellular messenger that has been suggested to play a major role in several different in vivo models of neuronal plasticity including learning. Within particular vestibulum-connected brain centers, significant effects of hyper-gravity were obtained, e.g., in the magnocellular nucleus, a primary vestibular relay ganglion of the brain stem octavolateralis area, in the superior rectus subdivision of the oculomotoric nucleus and within cerebellar eurydendroid cells, which in teleosts possibly resemble the deep cerebellar nucleus of higher vertebrates. Non-vestibulum related nuclei did not respond to hyper-gravity in a significant way. The effect of hyper-gravity found was much less distinct in adult animals as compared to the circumstances seen in larval fish (Anken et al., Adv. Space Res. 17, 1996), possibly due to a development correlated loss of neuronal plasticity.

Afferent Pathways↗

PubMed2004

Plasticity in single neuron and circuit computations.

Plasticity in neural circuits can result from alterations in synaptic strength or connectivity, as well as from changes in the excitability of the neurons themselves. To better understand the role of plasticity in the brain, we need to establish how brain circuits work and the kinds of computations that different circuit structures achieve. By linking theoretical and experimental studies, we are beginning to reveal the consequences of plasticity mechanisms for network dynamics, in both simple invertebrate circuits and the complex circuits of mammalian cerebral cortex.

Animals↗

PubMed1995

NMDA receptor redox sites: are they targets for selective neuronal protection?

NMDA receptors play a central role in neuronal plasticity and in several pathological situations. Transient activation of this receptor triggers long-term potentiation, whereas sustained activation leads to cell death. Evidence for control of this activity by a redox site in cell cultures, brain tissues and in recombinant NMDA receptors are discussed by Henri Gozlan and Yehezkel Ben-Ari. The characteristics of this modulation and the consequences of redox state modifications on NMDA-mediated events are examined in vitro under physiological and pathological conditions. Since metabolic disorders enhance NMDA receptor function, the redox site could constitute a new target for selectively preventing in vivo the deleterious consequences of overactivation without blocking neuronal plasticity mediated by NMDA receptors.

Alkylation↗

PubMed1999

Fos expression during the critical period in visual cortex: differences between normal and dark reared cats.

The present study tested further the notion that immediate early gene expression is involved in neuronal plasticity during the critical period of visual cortex (VC) by comparing Fos induction in normal and dark reared (DR) cats. Western blots indicated that the level of induced Fos expression was higher in normal than DR cat VC at 5 weeks of age, comparable at 10 weeks, and higher in DR than normal cat VC at 20 weeks. Immunohistochemistry indicated that at 5 weeks Fos was induced in cells of all VC layers in both rearing conditions, but to a greater extent in normal than DR cats. At 20 weeks, Fos was largely restricted to cells above and below layer IV in both rearing conditions, but was induced to a greater extent in DR than normal cats. Thus, dark rearing appears to have very similar effects on Fos expression as it has on neuronal plasticity during the postnatal critical period.

Animals↗

PubMed2005

Diurnal effects of enriched environment on immediate early gene expression in the rat brain.

Rodents housed in an enriched environment (EE) show increased neuronal plasticity with enhanced long-term potentiation and memory performance. We report an EE-induced increase in NGFI-A and Krox-20 mRNA expression exclusively during the dark period of the day. In addition, EE-housed rats showed considerable diurnal variation in NGFI-A, Krox-20, and NGFI-B mRNA expression which was absent in single-housed rats. Thus, EE-induced molecular changes are more evident during the dark phase when the rats have higher motor and exploratory activity. This is important to take into account in future studies of molecular mediators of experience-dependent neuronal plasticity.

Analysis of Variance↗

PubMed2005

Enhanced episodic-like memory and kindling epilepsy in a rat model of tuberous sclerosis.

Tuberous sclerosis complex (TSC) is a common neurological autosomal-dominant syndrome caused by mutations in the TSC1 or TSC2 genes. TSC starts in early childhood and is characterized by cerebral hamartomas (benign tumours), severe epilepsy and cognitive deficits such as mental retardation and autism. The hamartomas are characterized by loss of the remaining wild-type TSC allele, and clinical data implicate cerebral hamartomas in the generation of epileptic seizures, which may play a significant role in the development of mental retardation. The TSC2 mutation predicts alterations in mitogen-associated protein kinase (MAPK) and, together with the TSC1 mutation, in mammalian target of rapamycin (mTOR) signalling pathways. Both pathways are involved in neuronal plasticity. We therefore hypothesized that the heterozygous mutation itself, besides cerebral hamartomas, contributes to the pathogenesis of cognitive deficits and possibly also epilepsy. Here, we show that young adult TSC2+/- rats, which are virtually free of cerebral hamartomas, exhibit enhanced episodic-like memory and enhanced responses to chemically-induced kindling. The activation of cyclic adenosine monophosphate (cAMP) in the hippocampus results in stronger induction of phospho-p42-MAPK in TSC2+/- rats than in wild-type animals. Thus, the cognitive phenotype and, possibly, epilepsy in TSC patients may result not only from the focal hamartomatous lesions but also, from altered neuronal plasticity in the heterozygous tissue.

Alleles↗

PubMed1997

Spatial memory is related to hippocampal subcellular concentrations of calcium-dependent protein kinase C isoforms in young and aged rats.

Relationships were examined between spatial learning and hippocampal concentrations of the alpha, beta2, and gamma isoforms of protein kinase C (PKC), an enzyme implicated in neuronal plasticity and memory formation. Concentrations of PKC were determined for individual 6-month-old (n = 13) and 24-month-old (n = 27) male Long-Evans rats trained in the water maze on a standard place-learning task and a transfer task designed for rapid acquisition. The results showed significant relationships between spatial learning and the amount of PKC among individual subjects, and those relationships differed according to age, isoform, and subcellular fraction. Among 6-month-old rats, those with the best spatial memory were those with the highest concentrations of PKCgamma in the particulate fraction and of PKCbeta2 in the soluble fraction. Aged rats had increased hippocampal PKCgamma concentrations in both subcellular fractions in comparison with young rats, and memory impairment was correlated with higher PKCgamma concentrations in the soluble fraction. No age difference or correlations with behavior were found for concentrations of PKCgamma in a comparison structure, the neostriatum, or for PKCalpha in the hippocampus. Relationships between spatial learning and hippocampal concentrations of calcium-dependent PKC are isoform-specific. Moreover, age-related spatial memory impairment is associated with altered subcellular concentrations of PKCgamma and may be indicative of deficient signal transduction and neuronal plasticity in the hippocampal formation.

Aging↗

PubMed1998

Blockade of cholinergic receptors in rat barrel cortex prevents long-term changes in the evoked potential during sensory preconditioning.

We offer evidence that acetylcholine (ACh) is involved in the emergence of functional neuronal plasticity induced by whisker pairing. Evoked potentials were recorded within the barrel cortex of awake, adult rats before, during, and after one of five paradigms. In the pairing procedure, each of 50 deflections of a whisker (S1) was followed 150 ms later by the deflection of a second whisker (S2). The explicitly unpaired control procedure differed by the lack of contiguity and contingency between the stimulation of S1 and S2. In the three remaining groups, pairing was performed 30 min after an intraperitoneal injection of either 0.5 ml of saline (150 mM NaCl), 100 mg/kg of atropine methyl nitrate (0.5 ml of AMN in saline), or 100 mg/kg of atropine sulfate (0.5 ml of ATS in saline). Changes in responsiveness to S1 were compared with, and adjusted by, changes in responsiveness to stimulation of S2. Changes in potentials evoked by S1 were interpreted as a change in neuronal excitability occurring when the first innocuous stimulus systematically predicted the appearance of the second innocuous stimulus. When whisker pairing was performed alone or in the presence of either saline or AMN (a blocker of muscarinic cholinoreceptors that does not cross the blood-brain barrier, BBB), responses to S1 increased, whereas, in the presence of ATS (blocker of muscarinic cholinoreceptors that does cross the BBB) or following the explicitly unpaired control, they decreased. The effects of saline, AMN, and ATS on the evoked potential without vibrissae pairing were opposite to those observed when these substances were injected and pairing occurred. Analysis of the behavioral state of the animal showed that the changes observed in the evoked potential could not be attributed to changes in behavioral state. The changes in responsiveness to S1 induced by whisker pairing were independent of neuronal excitability, did not occur in the absence of contingency and contiguity between S1 and S2, were blocked by the muscarinic receptor antagonist ATS, but not by blockade of muscarinic modulation of normal synaptic transmission. Thus activation of muscarinic cholinoreceptors within the CNS were a necessary condition for this form of neuronal plasticity.

Animals↗

PubMedDate not supplied

Effect of unilateral dentate nucleus lesions on amygdaloid kindling in rats.

Amygdala kindling is used to investigate cerebellar dentate nucleus participation in the neuronal plasticity of the cerebrum. We studied the behavioral change, the occurrence of epileptiform events, and the duration of afterdischarge during amygdaloid kindling under control conditions and after a dentate lesion of the contralateral cerebellum. Our results indicate that the dentate lesion induced the facilitation of the behavioral development of the amygdaloid kindling, whereas there was only a slight increase in the duration of afterdischarge and the spontaneous epileptiform potential of the amygdala. There was a discrepancy between the behavioral kindling and the electroencephalographic epileptic activity. Therefore the dentate lesion must play a role in controlling the generalization mechanism of epilepsy. We also found that on a right amygdala that had been influenced by a left dentate lesion there were few spikes, while on the left amygdala there were frequent spikes. These results suggest that the dentate nucleus plays an important role in amygdaloid kindling as well as in the neuronal plasticity of the amygdala.

Amygdala↗

PubMed2002

Do apoptotic mechanisms regulate synaptic plasticity and growth-cone motility?

Signals between neurons are transduced primarily by receptors, and second messenger and kinase cascades, located in pre- and postsynaptic terminals. Such synaptic signaling pathways include those activated by neurotransmitters, cytokines, neurotrophic factors, and cell-adhesion molecules. Many of these signaling systems are also localized in the growth cones of axons and dendrites, where they control pathfinding and synaptogenesis during development. Although it has been known for decades that such signaling pathways can affect the survival of neurons, by promoting or preventing a form of programmed cell death known as apoptosis, we have discovered that apoptotic biochemical cascades can exert local actions on the functions and structural dynamics of growth cones and synapses. In this article, we provide a brief background on apoptotic biochemical cascades, and present examples of studies in this laboratory that have identified novel apoptotic and anti-apoptotic signaling mechanisms that are activated and act locally in synapses, growth cones, and dendrites to modify their structure and function. Apoptotic synaptic cascades that may play roles in neuronal plasticity include activation of caspases that can cleave certain types of ionotropic glutamate-receptor subunits and thereby modify synaptic plasticity. Caspases may also cleave cytoskeletal protein substrates in growth cones of developing neurons and may thereby regulate neurite outgrowth. Par-4 and the tumor-suppressor protein p53 are pro-apoptotic proteins that may also function in synaptic and developmental plasticity. Examples of anti-apoptotic signals that regulate the plasticity of growth cones and synapses include neurotrophic factor-activated kinase cascades, calcium-mediated actin depolymerization, and activation of the transcription factor NF-kappaB. The emerging data strongly suggest that many of the signaling mechanisms that control apoptosis are also involved in regulating the structural and functional plasticity of neuronal circuits under physiological conditions.

Animals↗

PubMed1995

Activation of arc, a putative "effector" immediate early gene, by cocaine in rat brain.

As immediate early genes (IEGs) are thought to play a critical role in mediating stimulus-induced neuronal plasticity, several laboratories have characterized the IEG response induced by cocaine to help define the changes in gene expression that may underlie its long-lasting behavioral effects. Although activation of several transcription factor IEGs has been described, little is known about which "effector" IEGs, if any, are also induced. In the present study, we have examined whether cocaine administration affects expression of a recently identified "effector" IEG, referred to as arc (activity-regulated, cytoskeleton-associated). This IEG encodes a protein with homology to spectrin that appears to be associated with the actin cytoskeleton. Using in situ hybridization, we have found that systemic cocaine administration elicits a robust, transient rise in arc mRNA levels in striatum, which is suppressed by D1 dopamine receptor blockade, reserpine treatment, or striatal 6-hydroxydopamine lesions. D2 receptor antagonist triggered arc expression when administered alone. Immunohistochemical studies indicated that Arc protein induced by cocaine is expressed in neuronal cell bodies and dendrites. As Arc appears to be component of the neuronal cytoskeleton, it may be involved in structural alterations underlying neuronal plasticity triggered by cocaine.

Animals↗

PubMed2004

Mitogen-activated protein kinase signaling.

The mechanism by which cells respond to extracellular stimuli involves a series of signal transduction events across the cell membrane and through the cytoplasm to the nucleus. Mitogen-activated protein (MAP) kinases are important mediators of signal transduction and play a key role in the regulation of many cellular processes, such as cell growth and proliferation, differentiation, and apoptosis. In mammalian cells, three major groups of MAP kinases have been identified: extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAP kinase. It is well documented that ERK is typically stimulated by growth-related signals, whereas the JNK and p38 MAP kinase cascades are activated by various stress stimuli. Studies have indicated that MAP kinases are expressed abundantly in the central nervous system (CNS) and that ERK is involved in long-lasting neuronal plasticity, including long-term potentiation and memory consolidation. While the role of ERK in neuronal plasticity and behavioral adaptation is beginning to emerge, the role of MAP kinase signal transduction cascades in major psychiatric disorders, including schizophrenia, is not well understood. This review outlines the intermediates of this signaling cascade and downstream transcription factor targets and recent evidence implicating MAP kinases to important biological functions in the CNS. Evidence from human post-mortem studies, as well as from the phencyclidine model of schizophrenia, that different MAP kinase cascades may be involved in the pathogenesis of schizophrenia, and potentially in other psychiatric disorders, is presented. Knowledge of MAP kinase signaling will aid greatly in our ability t o understand causal changes in disease process and may lead to new therapeutic approaches in controlling or treating schizophrenia.

Animals↗