Mechanisms Of Neuronal Plasticity Research Articles

Molecular cloning and expression regulation of PRG-3, a new member of the plasticity-related gene family.

Phospholipid-mediated signalling on neurons provokes diverse responses such as neurogenesis, pattern formation and neurite remodelling. We have recently uncovered a novel set of molecules in the mammalian brain, named plasticity-related genes (PRGs), which mediate lipid phosphate phosphatase activity and provide evidence for their involvement in mechanisms of neuronal plasticity. Here, we report on a new member of the vertebrate-specific PRG family, which we have named plasticity-related gene-3 (PRG-3). PRG-3 is heavily expressed in the brain and shows a specific expression pattern during brain development where PRG-3 expression is found predominantly in neuronal cell layers and is already expressed at embryonic day 16. In the mature brain, strongest PRG-3 expression occurs in the hippocampus and cerebellum. Overexcitation of neurons induced by kainic acid leads to a transient down-regulation of PRG-3. Furthermore, PRG-3 is expressed on neurite extensions and promotes neurite growth and a spreading-like cell body in neuronal cells and COS-7 cells. In contrast to previously described members of the PRG family, PRG-3 does not perform its function through enzymatic phospholipid degradation. In summary, our findings feature a new member of the PRG family which shows dynamic expression regulation during brain development and neuronal excitation.

Selective Regulation of Neurite Extension and Synapse Formation by the β but not the α 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 Ca 2+/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 CaMKIIβ, which peaks in expression early in development, but not CaMKIIα, has this morphogenic activity. A small insert in CaMKIIβ, which is absent in CaMKIIα, 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 CaMKIIα regulating synaptic strength and CaMKIIβ controlling the dendritic morphology and number of synapses .

Are NMDA receptors in the cortex affected by sensory learning?

NMDA receptor is a heteromeric, ligand‐gated calcium channel, believed to mediate mechanisms of neuronal plasticity. In the adult cerebral cortex the receptor is build up with NR1, NR2A and NR2B subunits. The properties of the receptor are regulated by changing the relative expression of NR2A and NR2B subunits. We have previously found that 3 days of classical conditioning in which stimulation of a row of vibrissae was paired with a tail shock induces NMDA‐receptor dependent changes in cortical representations of the stimulated vibrissae. Expression level of NR2A and NR2B subunits during training was examined by in situ hybridization. NR2A mRNA expression showed a rising tendency in the barrel (layer IV) of the ‘trained’ row of vibrissa after sensory conditioning. At the same time point, NR2A protein level in P2 fraction showed similar increasing tendency. NR2B expression level did not change. The results indicate that a short lasting learning‐dependent task induces a small modification in the composition of NMDA receptor channel complex.

Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory.

The hypothesis that synaptic plasticity is a critical component of the neural mechanisms underlying learning and memory is now widely accepted. In this article, we begin by outlining four criteria for evaluating the 'synaptic plasticity and memory (SPM)' hypothesis. We then attempt to lay the foundations for a specific neurobiological theory of hippocampal (HPC) function in which activity-dependent synaptic plasticity, such as long-term potentiation (LTP), plays a key part in the forms of memory mediated by this brain structure. HPC memory can, like other forms of memory, be divided into four processes: encoding, storage, consolidation and retrieval. We argue that synaptic plasticity is critical for the encoding and intermediate storage of memory traces that are automatically recorded in the hippocampus. These traces decay, but are sometimes retained by a process of cellular consolidation. However, we also argue that HPC synaptic plasticity is not involved in memory retrieval, and is unlikely to be involved in systems-level consolidation that depends on HPC-neocortical interactions, although neocortical synaptic plasticity does play a part. The information that has emerged from the worldwide focus on the mechanisms of induction and expression of plasticity at individual synapses has been very valuable in functional studies. Progress towards a comprehensive understanding of memory processing will also depend on the analysis of these synaptic changes within the context of a wider range of systems-level and cellular mechanisms of neuronal transmission and plasticity.

Apoptosis in the mechanisms of neuronal plasticity in the developing visual system.

Visual experience during early postnatal life is essential for normal development of synaptic connections in the visual system. In fact, altered visual experiences such as monocular deprivation (MD) or abnormal visual stimulation (e.g. strabismus, anisometropia) during this period disrupt the physiologic organization of the visual pathway, leading to loss of visual responses in cortical neurons and reduction in visual acuity of the affected eye, so that it becomes amblyopic. The authors review the main functional and morphologic changes induced by altered visual experiences in the developing visual system and focus on the recent discovery that MD induces apoptotic cell death in the lateral geniculate nucleus of newborn rats. Particular attention is given to the authors' studies documenting that, during development, MD leads retinal terminals to release excessive glutamate in the lateral geniculate nucleus where it elevates nitric oxide and causes DNA fragmentation. The latter event is known to activate poly-(ADP-ribose) polymerase, which in turn may trigger apoptosis. Better understanding of the mechanisms underlying the morphologic changes induced by altered visual experiences during development may open new venues for studying novel neuroprotective strategies for amblyopia and, more generally, for the treatment of ophthalmic diseases associated with neuronal apoptosis.

A Novel Mechanism of Dendritic Spine Plasticity Involving Estradiol Induction of Prostaglandin-E2

The mechanisms establishing and maintaining dendritic spines in the mammalian CNS remain primarily unknown. We report a novel mechanism of neuronal spine plasticity in the developing preoptic area in which estradiol induces prostaglandin-E2 (PGE2) synthesis that in turn increases the density of spine-like processes. Estradiol requires PGE2 synthesis, in vivo and in vitro, and upregulates the dendritic spine protein spinophilin, an effect attenuated by antagonism of the AMPA-kainate receptor. This signaling pathway may involve cross talk between neighboring neurons and astrocytes and appears specific to the preoptic area in that hippocampal neurons responded with an increase in spinophilin to estradiol but not PGE2. Regionally specific mechanisms of estradiol-mediated synaptic plasticity allow for epigenetic control of complex sex-typic behaviors.

The role of extracellular signal-regulated kinase in cognitive and motor deficits following experimental traumatic brain injury

Traumatic brain injury (TBI) causes neuronal death and alters the plasticity (e.g. morphology) of surviving neurons. Both of these events contribute to TBI-associated neurological deficits, such as memory dysfunction. Although a majority of current research is directed towards identifying biochemical cascades responsible for cell death, little is known about mechanisms of altered neuronal plasticity following TBI. Extracellular signal-regulated kinases (Erk1 and 2) play a critical role in growth and have been implicated in long-lasting neuronal plasticity and memory storage. The activation of Erk following TBI was investigated utilizing an antibody that specifically binds to dually phosphorylated Erk. Using this antibody, we report that lateral cortical impact injury in rats increases Erk phosphorylation both in the cortex and the hippocampus as early as 10 min post-injury. Double immunostaining experiments using either a neuron-specific or an astroglial-specific marker show that the active Erk is localized almost exclusively in neuronal cells. Furthermore, the increase in phospho-Erk immunoreactivity was initially localized to axons and at later time points was observed to be predominantly in the cell soma. This suggests that Erk redistributed over time and may play a role in retrograde signaling. Administration of inhibitors of the Erk cascade worsened retrograde amnesia, impaired performances in hippocampus- and amygdala-dependent memory tasks, and exacerbated motor deficits following TBI. Furthermore, inhibition of this cascade did not have any overt effects on cell survival, but altered neuronal morphology as detected by a dendritic-specific marker. These findings suggest that the Erk cascade plays an essential role for the maintenance of neuronal function and plasticity following TBI.

Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders.

As in other cells, neurons use adenosine triphosphate (ATP) as an energy source to drive biochemical processes involved in various cell functions, and produce reactive oxygen species (ROS) as "by products" of oxidative phosphorylation. However, the electrical excitability and structural and synaptic complexity of neurons present unusual demands upon cellular systems that produce or respond to ATP and ROS. Mitochondria in axons and presynaptic terminals provide sources of ATP to drive the ion pumps that are concentrated in these structures to rapidly restore ion gradients following depolarization and neurotransmitter release. Mitochondria may also play important roles in the regulation of synaptic function because of their ability to regulate calcium levels and ROS production. ROS generated in response to synaptic activity are now known to contribute to the regulation of long-term structural and functional changes in neurons, and the best-known example is the nitric oxide radical. The high-energy demands of synapses, together with their high levels of ROS production, place them at risk during conditions of increased stress, which occur in aging, neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, and after acute traumatic and ischemic insults. Energy depletion and/or increased oxidative damage to various synaptic proteins can result in a local dysregulation of calcium homeostasis and synaptic degeneration. Accordingly, recent studies have shown that dietary and pharmacological manipulations that improve energy efficiency and reduce oxyradical production can prevent synaptic degeneration and neuronal death in experimental models of neurodegenerative disorders. A better understanding of the molecular control of subcellular energy production and utilization, and of the functional relationships between energy metabolism, ion homeostasis, and cytoskeletal and vesicular dynamics, will provide novel insight into mechanisms of neuronal plasticity and disease.

The role of endogenous peptides in the development of long-term posttetanic potentiation

Using the model of long-term posttetanic potentiation (LTP) in slices of the olfactory cortex of rat brain, we have tested a hypothesis according to which activation of nerve cells results in a release of neuromodulatory factors into extracellular space; these factors, diffusing over significant distances, are capable of synchronously modifying the initial reactivity of neuronal populations. Using the technique of bioassay, i.e., transfer of perfusate from the tetanized donor slice to the recipient slice, in combination with pharmacological and neurochemical techniques, we found that in response to excitation, the cells of olfactory cortex slices secrete peptides. This observation confirms the above hypothesis. The spectrum of released peptides changes depending on the degree of cell excitation and, in addition, is frequency-dependent. It has been demonstrated that the key target of these peptides are N-methyl-D-aspartate and glutamate receptors. We propose that two peptide pools are involved in the initial and late phases of LTP. The possible significance of peptide cell regulation in mechanisms of neuronal plasticity is discussed.

Functional genomics in experimental and human temporal lobe epilepsy: powerful new tools to identify molecular disease mechanisms of hippocampal damage

The human genome project is a milestone for molecular genetic studies on complex, sporadic disorders in the human central nervous system (CNS). Functional analysis and tissue-/cell-specific expression profiles will be of particular importance anticipating the magnitude of expressed genes in the brain and their dynamic epigenetic modifications. The recent progress in microarray technologies allows expression studies for a large number of genes. In combination with laser-microdissection and quantitative reverse transcription-polymerase chain reaction technologies, such large-scale expression analyses can be successfully addressed in well-defined tissue specimens or cellular subpopulations. Complex, sporadic diseases, such as temporal lobe epilepsy (TLE), are challenging for functional genomics. Issues of particular importance in this field include molecular mechanisms of neurodevelopmental abnormalities, neuronal plasticity and hyperexcitability as well as neuronal cell damage in affected CNS areas. The availability of anatomically well-preserved surgical specimens, i.e. hippocampus obtained from epilepsy patients with Ammon's horn sclerosis or focal lesions not affecting the hippocampus proper as well as comparisons with experimental TLE models may help to elucidate specific molecular-pathological mechanisms during epileptogenesis and in chronic conditions of the disease.

Lateral magnocellular nucleus of the anterior neostriatum (LMAN) in the zebra finch: neuronal connectivity and the emergence of sex differences in cell morphology.

The song system of birds provides a model system to study basic mechanisms of neuronal plasticity and development underlying learned behavior. Song learning and production involve discrete sets of interconnected nuclei in the avian brain. One of these nuclei, the lateral magnocellular nucleus of the anterior neostriatum (LMAN), is the output of the so-called anterior forebrain pathway known to be essential for learning and maintenance of song, both processes depending on auditory feedback. In zebra finches, only males sing and this sexually dimorphic behavior is mirrored by sexual dimorphism in neuronal structure that develops during ontogeny. Female zebra finches are not able to sing and nuclei of the song system are strongly reduced in size or even lacking, when compared to male brains. Only LMAN can be delineated as easily in females as in males. Since female zebra finches, despite being unable to sing, recognize song just as males do and form a memory for song (model acquisition) early in life, LMAN is a putative candidate for song acquisition in both sexes. Therefore, development of LMAN was studied at the cellular and ultrastructural level in both male and female zebra finches. Regressive development of dendritic spines, enlargement of neuronal cell body and nuclei size, as well as changes at the nucleolar level are events all occurring exclusively in males, when song learning progresses. The decline in synapse number and the augmentation in synaptic contact length at synapses in LMAN in males are indicative for synaptic plasticity, whereas in females synapse number and synaptic contact length remain unchanged.

Regulated expression of the neuronal calcium sensor-1 gene during long-term potentiation in the dentate gyrus in vivo

Neuronal calcium sensor-1 (NCS-1), the mammalian homologue of frequenin, is a member of a highly conserved family of neuron-specific calcium-binding proteins which has been implicated in exocytosis and in multiple calcium-signalling pathways, suggesting a potential involvement in mechanisms of neuronal plasticity. Here, using in situ hybridization, we report an increased induction of the mRNA encoding NCS-1 in dentate granule cells following the induction of long-term potentiation in the awake rat. We show that NCS-1 mRNA levels are increased 1 and 3 h after long-term potentiation in an N-methyl- D-aspartate receptor-dependent manner, returning to baseline expression levels by 6 h. Electroconvulsive stimulation also induced NCS-1 mRNA transcription in the dentate gyrus, but at the different time of 6 h post-seizure, returning to baseline by 12 h. These results show that regulated expression of the NCS-1 gene is part of the transcriptional response associated with activity-dependent neuronal plasticity in vivo and suggest a molecular mechanism capable of mediating a functional change in synapse sensitivity to calcium and calcium-signalling pathways after long-term potentiation.

Visuospatial processing and training effects in Alzheimer's disease (AD) and healthy subjects assessed with fMRI

Fourteen AD patients and 14 healthy control subjects, matched for gender and age, were investigated with functional magnetic resonance imaging (WRI) during a visuospatial discrimination task. The task consisted of serially presented analogue clocks with the clock hands forming different angle sizes. All subjects were advised to press a button every time a specified angle occurred. The examination was carried out using a 1 .S Tesla MRI scanner. Fifteen slices covering the whole cortex were obtained every 4 seconds using a single-shot echo-planar (EPI) functional imaging sequence. We additionally examined a subsample of 5 patients and 5 controls which underwent three training sessions practicing the same task and who were re-examined one week after the initial fMRI measurement. ReSUlt.9 The task performance of AD patients and controls did not differ significantly. A specific fMRI activation pattern could be established for the control group, with a greater activation in the right superior parietal lobule (rSPL) compared to right primary visual cortex (rPVC). The AD group showed an inverse pattern with lower activation in the right superior parietal lobule (rSPL) than in rPVC. The subsample of trained controls revealed a significant reduction of BOLD signal change in right and left SPL after training. Only 3 of 5 trained patients showed a reduction of SPL activation after training, which was significantly smaller extent than in controls. Discussion These results correspond to neuropathological findings of differential damage to cortical areas of the visual system in AD. This study indicates that assessing local task related alterations of brain activity by fMR1 can help to elucidate the neurobiological and neuropathological mechanisms of AD. The results of the training study suggest a redundant activation in SPL in healthy subjects, which is lowered -perhaps owing to a more efficient use of cortical tissue - after training. A (albeit smaller) effect of practice could also be observed in some AD patients, which indicates that mechanisms of neuronal plasticity are preserved to some extent in AD.

Dendritic Alterations of Cerebellar Purkinje Neurons in Postnatally Lead-Exposed Kittens

Many investigations have sought to determine the effect of lead exposure on the development of the cerebellum. This study addresses the effects of postnatal lead exposure in kittens on dendritic development of Purkinje cells. Golgi-Cox filled cells were used to measure dendritic branching patterns, spine density, height, width and distance from the cerebellar surface. The results revealed a significant increase in spine density and altered patterns of dendritic branching. Complex dendritic branching was evident with a progressive shift in peak branching peripherally. Lead-exposed Purkinje cells showed early sprouting with subsequent pruning. At 5 weeks of age dendritic branches on experimental cells were increased along the entire dendritic extent. Control Purkinje cells showed initial sprouting with subsequent pruning. Normal developmental growth spurts and lead-induced effects were evident on dendritic height, width and distance from the surface. Cerebella stained with hematoxylin and eosin and cresyl violet acetate showed no evidence of vascular damage or other pathologies. These findings corroborate the evidence of hyperspiny dendritic formation representing an important mechanism of neuronal plasticity. In regard to morphological effects of lead on rodents, the hyperspiny Purkinje cell dendrites and patterns of dendritic growth in lead-treated kittens offer an alternative interpretation of neurobehavioral findings of lead-burdened children. The results are discussed with reference to other aspects of lead exposure and neural development.

Lesion‐induced changes of electrophysiological properties in astrocytes of the rat dentate gyrus

Reorganization of the adult dentate gyrus following unilateral entorhinal cortex lesion (ECL) is a well-established model for studying mechanisms of trauma-induced neuronal plasticity. The lesion induces deafferentiation of the outer molecular layer, which is accompanied by a strong astroglial reaction. This glial response is thought to contribute to subsequent repair processes, but the underlying mechanisms are poorly understood. In this study we addressed the question whether denervation leads to modifications in the electrophysiological properties of astrocytes, assuming that such changes might be involved in the remodeling of neural circuitry. Patch-clamp recordings were obtained from astrocytes in the dentate gyrus of adult rats that underwent ECL and compared to corresponding data from control animals. We observed a significant reduction of inward rectifier K+ current densities, a positive shift of resting potentials, and an increase in input resistance in astrocytes of the denervated molecular layer. Current densities were reduced between 6 and 19 days postlesion (dpl), reaching a minimum at 10 dpl. Voltage-gated outward K+ currents were not affected by the lesion. Inward rectifier K+ currents increase with maturation in astrocytes. Thus, our results provide evidence that, following ECL, mature astrocytes dedifferentiated and readapted an immature current pattern. Presumably, these changes lead to stronger and prolonged depolarization of glial cells and neurons in response to activity-dependent K+ release, which in turn might enhance the synthesis of neurotrophic factors and contribute to a permissive environment for neuronal reorganization. GLIA 28:166–174, 1999. © 1999 Wiley-Liss, Inc.

Lesion-induced changes of electrophysiological properties in astrocytes of the rat dentate gyrus

Reorganization of the adult dentate gyrus following unilateral entorhinal cortex lesion (ECL) is a well-established model for studying mechanisms of trauma-induced neuronal plasticity. The lesion induces deafferentiation of the outer molecular layer, which is accompanied by a strong astroglial reaction. This glial response is thought to contribute to subsequent repair processes, but the underlying mechanisms are poorly understood. In this study we addressed the question whether denervation leads to modifications in the electrophysiological properties of astrocytes, assuming that such changes might be involved in the remodeling of neural circuitry. Patch-clamp recordings were obtained from astrocytes in the dentate gyrus of adult rats that underwent ECL and compared to corresponding data from control animals. We observed a significant reduction of inward rectifier K(+) current densities, a positive shift of resting potentials, and an increase in input resistance in astrocytes of the denervated molecular layer. Current densities were reduced between 6 and 19 days postlesion (dpl), reaching a minimum at 10 dpl. Voltage-gated outward K(+) currents were not affected by the lesion. Inward rectifier K(+) currents increase with maturation in astrocytes. Thus, our results provide evidence that, following ECL, mature astrocytes dedifferentiated and readapted an immature current pattern. Presumably, these changes lead to stronger and prolonged depolarization of glial cells and neurons in response to activity-dependent K(+) release, which in turn might enhance the synthesis of neurotrophic factors and contribute to a permissive environment for neuronal reorganization.

PLASTICITY IN NERVE CELL FUNCTION.

In clinical practice it is becoming more and more evident that neuronal plasticity plays an important role not only in normal function, but also during pathophysiological events and regeneration in the CNS. Therefore, a book entitled Plasticity in Nerve Cell Function is of potential interest to many clinicians in the field. The book is a monograph written by one of the authorities in the field, Professor Platon Kostyuk, Director of the A. A. Bogomoletz Institute of Physiology, Kiev, Ukraine. It should be noted, however, that the emphasis of this book is on the basic, i.e. molecular and cellular mechanisms of neuronal plasticity with very little discussion concerning the link between neuronal plasticity and clinical practice. For many, the term neuronal plasticity has become more or less synonymous with synaptic plasticity, i.e. changes in the efficacy of synaptic transmission in the CNS. The aim of this book, however, is to discuss neuronal plasticity in its broad sense, including all aspects of neuronal function. As pointed out by the author in the preface of the book, this is a book about the …

Hippocampal synaptic plasticity and cognition.

Discoveries made over the past 20 years have greatly improved our understanding of how the brain functions. This article focuses on the relation between memory and cellular mechanisms of neuronal and synaptic plasticity in the hippocampus. Several studies indicate that the hippocampal formation is a crucial element of the neurobiological bases of higher cognitive function. Severe damage to the hippocampal formation is known to produce seemingly permanent anterograde amnesia. A generally accepted hypothesis in neurobiology has been that long-lasting activity-dependent changes in the efficacy of synaptic transmission in the mammalian brain are considered to be of fundamental importance for the development of neural circuitry and for the storage of information. The most compelling and reliable model for such changes has been long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus. Therefore, the possibility of the discovery and development of compounds that, by modulating hippocampal synaptic plasticity, would be useful for the management of dementia and amnesia.

Dendritic spine changes associated with hippocampal long-term synaptic plasticity.

Long-term enhancement of synaptic efficacy in the hippocampus is an important model for studying the cellular mechanisms of neuronal plasticity, circuit reorganization, and even learning and memory. Although these long-lasting functional changes are easy to induce, it has been very difficult to demonstrate that they are accompanied or even caused by morphological changes on the subcellular level. Here we combined a local superfusion technique with two-photon imaging, which allowed us to scrutinize specific regions of the postsynaptic dendrite where we knew that the synaptic changes had to occur. We show that after induction of long-lasting (but not short-lasting) functional enhancement of synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in control regions on the same dendrite or in slices where long-term potentiation was blocked, no significant spine growth occurred.

Sensory regulation of immediate-early genes c-fos and zif268 in monkey visual cortex at birth and throughout the critical period.

The postnatal development of ocular dominance columns (ODCs) in monkey visual cortex provides an exquisite model for studying mechanisms of experience-guided neuronal plasticity. While the presence of columns at birth in Old World monkeys is now well established, it remains unclear whether cortical neurons at this early stage are capable of modulating gene expression in response to changing sensory conditions. Using a set of monocular deprivation and stimulation protocols, we examined activity-driven expression of the immediate-early genes (IEGs) c-fos and zif268 during the critical period of development. We observed well-delineated patterns of ODCs produced by sensory regulation of both IEGs throughout the critical period, starting as early as the first postnatal day. The expression levels are similar in layers II/II, IVC and VI throughout development, with no selective decline in the thalamorecepient layer (layer IVC) of adult monkeys. A narrow strip of non-columnar c-Fos expression was observed at the border of layers IVC and V. Our results show that neurons in monkey visual cortex are equipped at birth with the molecular machinery for coupling sensory inputs to active genomic responses and that this responsivity extends throughout the critical period. The findings are discussed within the context of a possible role for IEGs in sensory-driven cortical plasticity during development.