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PubMed1999

Activity and injury-dependent expression of inducible transcription factors, growth factors and apoptosis-related genes within the central nervous system.

This review primarily discusses work that has been performed in our laboratories and that of our direct collaborators and therefore does not represent an exhaustive review of the current literature. Our aim is to further discuss the role that gene expression plays in neuronal plasticity and pathology. In the first part of this review we examine activity-dependent changes in the expression of inducible transcription factors (ITFs) and neurotrophins with long-term potentiation (LTP) and kindling. This work has identified particular ITFs (Krox-20 and Krox-24) and neurotrophin systems (particularly the brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase-B, Trk-B system) that may be involved in stabilizing long-lasting LTP (i.e. LTP3). We also show that changes in the expression of other ITFs (Fos, Jun-D and Krox-20) and the BDNF/trkB neurotrophin system may play a central role in the development of hippocampal kindling, an animal model of human temporal lobe epilepsy. In the next part of this review we examine changes in gene expression after neuronal injuries (ischemia, prolonged seizure activity and focal brain injury) and after nerve transection (axotomy). We identify apoptosis-related genes (p53, c-Jun, Bax) whose delayed expression selectively increases in degenerating neurons, further suggesting that some forms of neuronal death may involve apoptosis. Moreover, since overexpression of the tumour-suppressor gene p53 induces apoptosis in a wide variety of dividing cell types we speculate that it may perform the same function in post-mitotic neurons following brain injuries. Additionally, we show that neuronal injury is associated with rapid, transient, activity-dependent expression of neurotrophins (BDNF and activinA) in neurons, contrasting with a delayed and more persistent injury-induced expression of certain growth factors (IGF-1 and TGFbeta) in glia. In this section we also describe results linking ITFs and neurotrophic factor expression. Firstly, we show that while BDNF and trkB are induced as immediate-early genes following injury, the injury-induced expression of activinA and trkC may be regulated by ITFs. We also discuss whether loss of retrograde transport of neurotrophic factors such as nerve growth factor following nerve transection triggers the selective and prolonged expression of c-Jun in axotomized neurons and whether c-Jun is responsible for regeneration or degeneration of these axotomized neurons. In the last section we further examine the role that gene expression may play in memory formation, epileptogenesis and neuronal degeneration, lastly speculating whether the expression of various growth factors after brain injury represents an endogenous neuroprotective response of the brain to injury. Here we discuss our results which show that pharmacological enhancement of this response with exogenous application of IGF-1 or TGF-beta reduces neuronal loss after brain injury.

Animals↗
PubMed2005

Sigma-1 receptor as regulator of neuronal intracellular Ca2+: clinical and therapeutic relevance.

Preserving brain function and cognitive faculties during aging and psychiatric diseases (e.g. psychotic, anxiety and affective disorders, dementia) is essential for the self-reliance and quality of life of patients. Cognitive loss involves not only memory, but also motor function. The decrease of catecholaminergic and excitatory neurotransmissions, as well as of protein phosphorylation, have currently been identified as prominent biological markers of the above-mentioned diseases. Such deleterious biological events are well known to occur downstream of a progressive decline of intracellular Ca2+ signalling. This latter constitutes a key target for the neuronal plasticity that has also been reported during aging and psychiatric disorders. Most of the medicines used in psychiatry are active on the sigma-1 receptor. This membrane bound receptor is widely distributed in memory-associated cortical and motor-related brainstem areas, prompting the hypothesis that it might contribute to the pathophysiology of these behavioural brain diseases. The sigma-1 receptor is characterized by a unique mode of action by regulating both Ca2+ entry at the plasma membrane level (i.e. via potassium channels, voltage-sensitive Ca2+ channels) and Ca2+ mobilization from endoplasmic stores [i.e. via Ins(1,4,5)P3 receptors]. This review presents recent data supporting the notion that drugs acting via the endoplasmic reticulum-coupled sigma-1 receptor might reverse these deleterious events by restoring both extra- and intra-cellular Ca(2+)-dependent neuronal responses.

Aging↗
PubMed2002

Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice.

In the brain of Alzheimer's disease (AD) patients, neurotoxic amyloid peptides accumulate and are deposited as senile plaques. A major therapeutic strategy aims to decrease production of amyloid peptides by inhibition of gamma-secretase. Presenilins are polytopic transmembrane proteins that are essential for gamma-secretase activity during development and in amyloid production. By loxP/Cre-recombinase-mediated deletion, we generated mice with postnatal, neuron-specific presenilin-1 (PS1) deficiency, denoted PS1(n-/-), that were viable and fertile, with normal brain morphology. In adult PS1(n-/-) mice, levels of endogenous brain amyloid peptides were strongly decreased, concomitant with accumulation of amyloid precursor protein (APP) C-terminal fragments. In the cross of APP[V717I]xPS1 (n-/-) double transgenic mice, the neuronal absence of PS1 effectively prevented amyloid pathology, even in mice that were 18 months old. This contrasted sharply with APP[V717I] single transgenic mice that all develop amyloid pathology at the age of 10-12 months. In APP[V717I]xPS1 (n-/-) mice, long-term potentiation (LTP) was practically rescued at the end of the 2 hr observation period, again contrasting sharply with the strongly impaired LTP in APP[V717I] mice. The findings demonstrate the critical involvement of amyloid peptides in defective LTP in APP transgenic mice. Although these data open perspectives for therapy of AD by gamma-secretase inhibition, the neuronal absence of PS1 failed to rescue the cognitive defect, assessed by the object recognition test, of the parent APP[V717I] transgenic mice. This points to potentially detrimental effects of accumulating APP C99 fragments and demands further study of the consequences of inhibition of gamma-secretase activity. In addition, our data highlight the complex functional relation of APP and PS1 to cognition and neuronal plasticity in adult and aging brain.

Alzheimer Disease↗
PubMed2006

Neurotrophic factors in the central nucleus of amygdala may be organized to provide substrates for associative learning.

The central nucleus of amygdala was examined to identify the ultrastructural distribution of neurotrophins responsible for the complex of neuronal signaling processes which regulate synaptic transmission and neuronal plasticity, and possibly underlie memory formation. We investigated at the electron microscopic level the cellular organization of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), in the extended amygdala (CE). We also investigated the interaction between cortical inputs to CE and BDNF and TrkB. Our results indicate the presence of pro-BDNF and BDNF in terminals in the CE which show a strong association with immunoreactive postsynaptic densities. TrkB receptor immunoreactivity was localized to postsynaptic densities of asymmetric synapses on dendrites and dendritic spines. Cortical terminals formed asymmetric synapses with dendritic shafts and spines, but were not BDNF immunoreactive. TrkB receptors were observed opposed to cortical terminals. These data also suggest that one potential substrate for associative learning may be the interaction of different cortical inputs with neurotrophin-containing terminals ending on dendritic spines and other neuronal structures of CE.

Amygdala↗
PubMed1995

AP-1 transcription factor complexes in CNS disorders and development.

Transcription factors are regulatory proteins that modify gene expression. Any cellular function requiring alterations in mRNA levels depends upon these factors. The CNS, AP-1 (activator protein-1; c-fos and fos-related antigens plus jun-related factors) and CREB (cAMP responsive element binding protein) families of transcription factors have been extensively studied. The DNA binding complex is composed of dimers formed between the AP-1 and CREB factors and binding specificity is dictated by which proteins comprise the complex. Whereas the AP-1 factors are inducible, CREB and related proteins are constitutive and regulate gene transcription through phosphorylation. Due to seizure activity, many AP-1 factors are induced, but rapidly return to basal levels. However, if neuronal death occurs, fos-related antigens of 35 kDa persist for an extended period and may be involved in regulating genes related to neuronal plasticity. Similar factors are expressed after chronic drug treatment indicating a role in drug tolerance. However, during early CNS development, elevated AP-1 DNA binding consisting of c-jun and CREB occurs in every brain region and is inversely related to the degree of maturation of a particular brain area. These transcription factors are important for gene regulation during CNS dysfunction and development and those present specify which genes are activated.

Activating Transcription Factor 2↗
PubMed1996

Neural unit activity in the trigeminal complex with interpositus or red nucleus inactivation during classical eyeblink conditioning.

During classical conditioning, many neurons in the trigeminal complex of rabbits exhibit activity that is related to the conditioned stimulus (tone), the unconditioned stimulus (airpuff), or to the conditioned response (eyeblink). For these reasons the trigeminal complex has been hypothesized to be a brainstem locus for the neuronal plasticity associated with conditioning. In this experiment, the learning-related activity (unit activity associated with the conditioned response) in the trigeminal is abolished when either the red nucleus or interpositus nucleus of the cerebellum is temporarily inactivated by cooling, but the stimulus-evoked activity is unaffected by cooling. This study and previous results support the suggestion that the learning-related activity seen in the trigeminal is driven by the interpositus by way of the red nucleus.

Animals↗
PubMed2006

Testosterone induces neuroprotection from oxidative stress. Effects on catalase activity and 3-nitro-L-tyrosine incorporation into alpha-tubulin in a mouse neuroblastoma cell line.

3-nitro-L-tyrosine is formed by nitric oxide following different pathways such as NADPH oxidase, xanthine oxidase or glutamate NMDA receptor activation and is involved in the pathology of different neurological disorders. Unlike estradiol, a neuroprotective role of androgens against oxidative cell injury has not been fully investigated. This work targets the possible effects of testosterone on neuroblastoma cells exposed to 3-nitro-L-tyrosine. C1300 mouse undifferentiated neuroblastoma cells exposed to 3-nitro-L-tyrosine were cultured in the presence of testosterone. Morphological examination, proliferation and nuclear viability assays were performed. The expression of tyrosinated alpha-tubulin and incorporation of 3-nitro-L-tyrosine into protein were also estimated. Cells exposed to 3-nitro-L-tyrosine showed globular shape, reduced cytoplasmic processes and growth inhibition in comparison with controls. When testosterone was added to the medium, these changes were not evident. In addition, testosterone induced an upregulation of tyrosinated alpha-tubulin, a marker of neuronal plasticity, and a decrease in 3-nitro-L-tyrosine incorporation into tubulin. Our results suggest that testosterone exposure can diminish 3-nitro-L-tyrosine toxic effects on the morphology and growth rate of neuroblastoma cells. The upregulation of tyrosinated alpha-tubulin in testosterone-exposed cells would be consistent with concurrent plasticity events. Failure in alpha-tubulin nitration detected in cells exposed to both 3-nitro-L-tyrosine and testosterone, may support the idea that testosterone interferes with 3-nitro-L-tyrosine protein incorporation. Moreover, testosterone-induced neuroprotection likely entails a linkage with the androgen receptor as is suggested by the flutamide-induced inhibition of the hormone activity. Finally, the neuroprotective effects of testosterone in neuroblastoma cells could deal with the cellular antioxidant defence system, as shown by testosterone-induced increase in catalase activity.

Androgen Antagonists↗
PubMed2004

Cyclin S: a new member of the cyclin family plays a role in long-term memory.

Memory is thought to be subserved by structural and functional alteration in synaptic connectivity. But although neuronal plasticity requires gene expression, the identity of the proteins involved is largely unknown. Using the chick 1-day-old passive avoidance learning paradigm and differential display RNA fingerprinting, we identified 13 candidate genes which are upregulated in the intermediate medial hyperstriatum ventrale (IMHV), an area that has been correlated with the initial processing of memory formation. One of the induced genes is a new member of the cyclin family, with high homology to cyclin L (ania-6a). Analysis of the expression pattern of this gene after training revealed two time waves of induction: the first correlated with learning and initial memory process in the IMHV; the second correlated with memory consolidation, first in the IMHV, and then in the lobus paraolefactoris. There is a correlation between methylanthranilate (MeA) concentrations (the malaise substrate in the passive avoidance training procedure), the duration of memory and the expression level of cyclin S. While training chicks on low concentrations of MeA causes short-term memory and low expression level of cyclin S, high concentration of MeA induces long-term memory and high expression level of cyclin S in the IMHV. The role of cyclins in the regulation of neuronal-plasticity-related gene expression was overlooked, and it might serve as a key step in long-term memory formation.

Amino Acid Sequence↗
PubMed2004

Eph/ephrin signaling in morphogenesis, neural development and plasticity.

Ephrins are cell-surface-tethered ligands for Eph receptors, the largest family of receptor tyrosine kinases. During development, the Eph/ephrin cell communication system appears to influence cell behavior such as attraction/repulsion, adhesion/de-adhesion and migration, thereby influencing cell fate, morphogenesis and organogenesis. During adulthood, the Eph/ephrin system continues to play roles in tissue plasticity, for example in shaping dendritic spines during neuronal plasticity. Mechanistically, Eph-ephrin repulsive behavior appears to require ligand-receptor internalization and signaling to Rho GTPases.

Animals↗
PubMed1998

Effect of neonatal exposure to monosodium L-glutamate on regional GABA release during postnatal development.

Monosodium L-glutamate (MSG) causes neuronal lesions in certain brain regions when systemically given to young animals. Also, when glutamate (Glu) builds up in the intersynaptic space, it induces neuroexcitatory and neurocytotoxic effects, events mediated by several Glu receptors. Some of these receptors such as NMDA and AMPA receptors are present in the very earliest developmental stages of the central nervous system and play a major role in neuronal plasticity during synaptogenesis. In this paper, the GABAergic system vulnerability was determined in terms of [3H]-GABA release during postnatal development. [3H]-GABA release on days 14, 21, 30, and 60 days after birth was assessed for the cerebral cortex (CC), hippocampus (Hp) and striatum (S) in rats perinatally treated at days 1, 3, 5, and 7 after birth with MSG. The results show a major decrease in baseline [3H]-GABA release in the CC (30 and 60 days after birth) and the Hp (beginning day 21 after birth) vs the control groups [intact rats and rats given a NaCl solution equimolar to that of MSG (eqNaCl)] while in the S baseline release remained unchanged. Stimulated [3H]-GABA release was decreased in the CC on days 14 and 21 after birth and significantly increased on day 60 after birth vs the controls. In the Hp, a decrease was seen on days 14, 21, and 60 after birth vs the controls while stimulated [3H]-GABA release was decreased in the S vs the controls at all ages studied. No significant differences in stimulated [3H]-GABA release were found between the intact group and the group treated with eqNaCl on days 30 and 60 after birth. Results show that CC, Hp and S GABAergic neurones are a major target for the effect of perinatally given MSG and suggest a possible decrease in the number of Hp GABAergic neurones while these results in CC and S suggest a modified neuronal plasticity. NMDA receptor and calcium involvement are discussed as significant mediators of these events.

Aging↗
PubMed1992

Phenotypic plasticity in adult sympathetic neurons: changes in neuropeptide expression in organ culture.

Vasoactive intestinal peptide (VIP)-like immunoreactivity is present at low levels in the superior cervical ganglion of the adult rat, where immunostained neural processes, but only an occasional immunostained cell body, are found. However, when ganglia are maintained for 24 or 48 hr in organ culture, their content of VIP-like immunoreactivity increases 6- or 31-fold, respectively. When examined at 24 hr, the increase in VIP-like immunoreactivity is totally blocked by an inhibitor of RNA or protein synthesis. Many neuronal cell bodies and processes with immunoreactivity for VIP and the related peptide histidine isoleucine amide (PHI) are seen in cultured ganglia. In addition, VIP/PHI mRNA is abundant in cultured ganglia but only barely detectable in ganglia prior to culture. Under the same culture conditions, neuropeptide Y-like immunoreactivity increases to a small extent, and tyrosine hydroxylase activity and total ganglion protein remain unchanged. These results support the idea that adult sympathetic neurons exhibit plasticity in neuropeptide expression and that this plasticity, in the case of VIP, depends on changes in gene expression.

Age Factors↗
PubMedDate not supplied

[Memory-linked morphological changes].

INTRODUCTION: It has been suggested that storing information in the brain takes place by means of changes in synaptic communication efficiency, which is known as neuronal plasticity. Plastic events include changes in the function, structure, distribution and number of synapses, and it has been suggested that these plastic events could be related to learning and memory. DEVELOPMENT: In this work we will review some studies that report structural changes in which experience and learning intervene. In particular, structural changes have been observed in a region of the brain called the hippocampus, which plays a crucial role in the learning and memory of spatial tasks. It has been claimed that the appearance of new synapses after learning a spatial task is linked to the formation of long-term memory and that the functioning of NMDA-type glutamate receptors is needed for both learning and the formation of new synapses to take place. CONCLUSIONS: Understanding the cellular mechanisms involved in the formation of memory is of utmost importance to be able to check the memory deficiencies that arise from injuries or as a consequence of old age and neurodegenerative diseases.

Animals↗
PubMed1985

Plasticity of hippocampal circuitry in Alzheimer's disease.

Two markers of neuronal plasticity were used to compare the response of the human central nervous system to neuronal loss resulting from Alzheimer's disease with the response of rats to a similar neuronal loss induced by lesions. In rats that had received lesions of the entorhinal cortex, axon sprouting of commissural and associational fibers into the denervated molecular layer of the dentate gyrus was paralleled by a spread in the distribution of tritiated kainic acid-binding sites. A similar expansion of kainic acid receptor distribution was observed in hippocampal samples obtained postmortem from patients with Alzheimer's disease. An enhancement of acetylcholinesterase activity in the dentate gyrus molecular layer, indicative of septal afferent sprouting, was also observed in those patients with a minimal loss of cholinergic neurons. These results are evidence that the central nervous system is capable of a plastic response in Alzheimer's disease. Adaptive growth responses occur along with the degenerative events.

Acetylcholinesterase↗
PubMed2004

Fasting-induced activation of mitogen-activated protein kinases (ERK/p38) in the mouse hypothalamus.

Activity-dependent changes in neuronal plasticity depend critically on gene regulation. To understand how fasting-induced stimulation leads to gene regulation through intracellular signalling pathways, we investigated the effect of fasting on activation of the mitogen-activated protein kinase (MAPK) family, the extracellular signal-regulated kinase (ERK) and the p38 MAPK (p38) in mouse hypothalamus. In the hypothalamic arcuate nucleus, phosphorylation of ERK significantly increased during fasting, spatially coincident with phosphorylation of cAMP response element binding protein (CREB), induction of c-Fos, and expression of neuropeptide Y (NPY). In the paraventricular nucleus (PVN) of fasted mice, activation of p38 in addition to ERK was also observed. In the arcuate nucleus of ob/ob mice, phosphorylations of ERK and CREB were decreased during fasting, whereas the expression of NPY was increased. In the PVN, increased activation of p38 was observed in spite of decreased activation of ERK. These results suggest that ERK and p38 are differentially activated by fasting in distinct regions of the hypothalamus depending on the condition of energy balance.

Animals↗
PubMed2005

Intrinsic membrane properties of vertebrate vestibular neurons: function, development and plasticity.

Central vestibular neurons play an important role in the processing of body motion-related multisensory signals and their transformation into motor commands for gaze and posture control. Over recent years, medial vestibular nucleus (MVN) neurons and to a lesser extent other vestibular neurons have been extensively studied in vivo and in vitro, in a range of species. These studies have begun to reveal how their intrinsic electrophysiological properties may relate to their response patterns, discharge dynamics and computational capabilities. In vitro studies indicate that MVN neurons are of two major subtypes (A and B), which differ in their spike shape and after-hyperpolarizations. This reflects differences in particular K(+) conductances present in the two subtypes, which also affect their response dynamics with type A cells having relatively low-frequency dynamics (resembling "tonic" MVN cells in vivo) and type B cells having relatively high-frequency dynamics (resembling "kinetic" cells in vivo). The presence of more than one functional subtype of vestibular neuron seems to be a ubiquitous feature since vestibular neurons in the chick and frog also subdivide into populations with different, analogous electrophysiological properties. The ratio of type A to type B neurons appears to be plastic, and may be determined by the signal processing requirements of the vestibular system, which are species-variant. The membrane properties and discharge pattern of type A and type B MVN neurons develop largely post-natally, through the expression of the underlying ion channel conductances. The membrane properties of MVN neurons show rapid and long-lasting plastic changes after deafferentation (unilateral labyrinthectomy), which may serve to maintain their level of activity and excitability after the loss of afferent inputs.

Action Potentials↗
PubMed1994

Plasticity of postganglionic sympathetic neurons in the rat superior cervical ganglion after axotomy.

The neuropeptides galanin (GAL) and vasoactive intestinal polypeptide (VIP) are upregulated in spinal and vagal sensory as well as in cranial motor neurons after axonal transection. In this study an increase of both peptides is demonstrated in axotomized principal ganglionic neurons (PGN) of the rat sympathetic superior cervical ganglion by use of double-labeling immunofluorescence. Compared to control ganglia that do not contain more than 1% GAL- or VIP-positive cells, about 26% of all PGN exhibit GAL immunoreactivity by day 1 after transection of the major postganglionic branches. The proportion of immunoreactive neurons reaches its maximum after 30 days (40%) and decreases to about 27% within the second month after axotomy. The percentage of VIP-positive neurons is much lower than for GAL: 2% of the PGN exhibit VIP immunoreactivity at day 1 and about 7% are observed 30 and 60 days after axotomy. In order to further characterize newly GAL- and VIP-positive PGN, their cell diameters were determined 12 days after axotomy. Compared to the mean overall neuron diameter of 24.8 microns, GAL-immunoreactive neurons are predominantly of small and intermediate size (22.2 microns), whereas VIP occurs mainly in larger neurons (26.1 microns). Besides cell bodies, many intraganglionic nerve fibers stain positive for GAL or VIP, particularly at day 6. Most likely, these fibers represent axons, as indicated by the absence of MAP2, a cytoskeletal protein found in neuronal somata and dendrites. They establish direct membrane contacts with postganglionic perikarya, as revealed by pre-embedding immuno-electron microscopy. Some cell bodies and fibers contain both peptides. Colocalization of GAL or VIP with tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine synthesis, reveals a reduced immunoreactivity for TH in intensely GAL- or VIP-positive cells, and vice versa at day 6. However, no difference in staining intensity for VIP or GAL, and TH, is observed after 30 and 60 days. Possible implications of GAL and VIP for peripheral nerve regeneration and their regulation by target-derived factors are discussed.

Animals↗
PubMed1977

Response plasticity of neurons in auditory cortex of the rhesus monkey.

Auditory-evoked responses in single neurons from rhesus monkey auditory cortex were measured under four relatively well defined behavioral and physiological conditions: (1) monkey awake and performing a simple auditory reaction time task; (2) monkey awake but not performing a task (Stage A); (3) monkey in a drowsy or Stage 1 sleep state (State B); and (4) monkey anesthetized with a short-acting nonbarbiturate anesthetic. For most units studied the response evoked by the auditory stimulus was greater in the performance condition than in the nonperformance condition. Similarly, evoked activity was usually greater in State A than in State B. Finally, evoked responses under anesthesia were usually weaker than those obtained in the unanesthetized animal. Some exceptions were noted in each case. Differences in response patterns and in rate versus intensity functions of neurons were also found to be associated with the behavioral and physiological state of the preparation. No significant changes in unit spontaneous activity associated with changes in behavioral or physiological condition were observed.

Acoustic Stimulation↗