Role In Developmental Plasticity Research Articles

Age-specific effects of early MK-801 treatment on working memory in female rats

The N-methyl-D-aspartate receptor plays a crucial role in developmental plasticity. Evidence shows that neonatal exposure to N-methyl-D-aspartate receptor antagonists impairs cognition in adult rats. This study investigated whether neonatal MK-801 treatment would produce long-term and age-specific effects on working memory and sensorimotor gating in adolescent and adult female rats. After treatment with MK-801 at postnatal days (PND) 5-14, female rats exhibited slightly impaired working memory during adolescence (PND: 35-42). In contrast, working memory was remarkably disrupted in adult (PND: 63-70) female rats. However, prepulse inhibition and startle amplitudes were not significantly affected at both ages. These findings indicate that neonatal MK-801 elicits working memory deficits, especially in the postpuberty female rats.

An endoplasmic reticulum response pathway mediates programmed cell death of root tip induced by water stress in Arabidopsis

Drought induces root death in plants; however, the nature and characteristics of root cell death and its underlying mechanisms are poorly understood. Here, we provide a systematic analysis of cell death in the primary root tips in Arabidopsis during water stress. Root tip cell death occurs when high water deficit is reached. The dying cells were first detected in the apical meristem of the primary roots and underwent active programmed cell death (PCD). Transmission electron microscopic analysis shows that the cells undergoing induced death had unambiguous morphological features of autophagic cell death, including an increase in vacuole size, degradation of organelles, and collapse of the tonoplast and the plasma membrane. The results suggest that autophagic PCD occurs as a response to severe water deficit. Significant accumulation of reactive oxygen species (ROS) was detected in the stressed root tips. Expression of BAX inhibitor-1 (AtBI1) was increased in response to water stress, and atbi1-1 displayed accelerated cell death, indicating that AtBI1 and the endoplasmic reticulum (ER) stress response pathway both modulate water stress-induced PCD. These findings form the basis for further investigations into the mechanisms underlying the PCD and its role in developmental plasticity of root system architecture and subsequent adaptation to water stress.

Heterosynaptic Facilitation of In Vivo Thalamocortical Long-Term Potentiation in the Adult Rat Visual Cortex by Acetylcholine

Acetylcholine (ACh) plays a permissive role in developmental plasticity of fibers from the lateral geniculate nucleus (LGN) to the primary visual cortex (V1). These fibers remain plastic and express long-term potentiation (LTP) in adult rodents, but it is not known if ACh modulates this form of plasticity in the mature V1. We show that, in anesthetized rats, theta burst stimulation (TBS) of the LGN using 5 or 40 theta cycles produced moderate (approximately 20%) and stronger (approximately 40%) potentiation, respectively, of field postsynaptic potentials recorded in the ipsilateral V1. Basal forebrain stimulation (100 Hz) 5 min after TBS enhanced LTP induced by both weak (5 theta cycles) and strong (40 theta cycles) induction protocols. Both effects were reduced by systemic administration of the muscarinic receptor antagonist scopolamine. Basal forebrain stimulation did not enhance LTP when applied 30 min after or 5 min prior to TBS, suggesting that ACh affects early LTP induction mechanisms. Application of the cholinergic agonist carbachol in V1 by means of reverse microdialysis mimicked the effect of basal forebrain stimulation. We conclude that heterosynaptic facilitation of V1 plasticity by ACh extends beyond early postnatal maturation periods and acts to convert weak potentiation into pronounced, long-lasting increases in synaptic strength.

Synaptic and genomic responses to JNK and AP-1 signaling in Drosophila neurons

BackgroundThe transcription factor AP-1 positively controls synaptic plasticity at the Drosophila neuromuscular junction. Although in motor neurons, JNK has been shown to activate AP-1, a positive regulator of growth and strength at the larval NMJ, the consequences of JNK activation are poorly studied. In addition, the downstream transcriptional targets of JNK and AP-1 signaling in the Drosophila nervous system have yet to be identified. Here, we further investigated the role of JNK signaling at this model synapse employing an activated form of JNK-kinase; and using Serial Analysis of Gene Expression and oligonucleotide microarrays, searched for candidate early targets of JNK or AP-1 dependent transcription in neurons.ResultsTemporally-controlled JNK induction in postembryonic motor neurons triggers synaptic growth at the NMJ indicating a role in developmental plasticity rather than synaptogenesis. An unexpected observation that JNK activation also causes a reduction in transmitter release is inconsistent with JNK functioning solely through AP-1 and suggests an additional, yet-unidentified pathway for JNK signaling in motor neurons. SAGE profiling of mRNA expression helps define the neural transcriptome in Drosophila. Though many putative AP-1 and JNK target genes arose from the genomic screens, few were confirmed in subsequent validation experiments. One potentially important neuronal AP-1 target discovered, CG6044, was previously implicated in olfactory associative memory. In addition, 5 mRNAs regulated by RU486, a steroid used to trigger conditional gene expression were identified.ConclusionThis study demonstrates a novel role for JNK signaling at the larval neuromuscular junction and provides a quantitative profile of gene transcription in Drosophila neurons. While identifying potential JNK/AP-1 targets it reveals the limitations of genome-wide analyses using complex tissues like the whole brain.

Areal and Subcellular Localization of the Ubiquitous Alkaline Phosphatase in the Primate Cerebral Cortex: Evidence for a Role in Neurotransmission

The ubiquitous enzyme TNAP (tissue non-specific alkaline phosphatase) is found in numerous tissues such as liver, kidney and bone, but little attention has been paid to its expression and role in the brain. Observations in TNAP-KO mice, which analyzed the role of this enzyme in osteogenesis, had suggested that TNAP might be involved in GABA neurotransmission. Apart from its presence in endothelial cells, here we show a specific and strong alkaline phosphatase (AP) activity in the neuropile, matching the pattern of thalamo-cortical innervation in layer 4 of the primate sensory cortices (visual, auditory and somatosensory). Such a pattern is also evident in rodents and carnivores, making AP a powerful marker of primary sensory areas. Remarkably, AP activity is regulated by sensory experience as demonstrated by monocular deprivation paradigms in monkeys. The areal and laminar distribution of AP activity matches that of the GAD(65), the GABA synthesizing enzyme found in presynatic terminals. As our electron microscopic investigations indicate that AP is found at the neuronal membranes and in synaptic contacts, it is proposed that the neuronal AP isoform (NAP), may be a key enzyme in regulating neurotransmission and could therefore play an important role in developmental plasticity and activity-dependent cortical functions.

Endocrine Mechanisms Underlying Plasticity in Metamorphic Timing in Spadefoot Toads

Amphibian larvae respond to heterogeneous environments by varying their rates of growth and development. Several amphibian species are known to accelerate metamorphosis in response to pond drying or resource restriction. Some of the most extensive studies to date on developmental responses to pond drying have been conducted on species of spadefoot toads (family Pelobatidae). We have found that tadpoles of two species of spadefoot toad accelerate metamorphosis when exposed to water volume reduction in the laboratory (to simulate a drying pond). Furthermore, Western spadefoot toad (Spea hammondii) tadpoles accelerated metamorphosis in response to food restriction, which was intended to simulate a decline in resource availability in the larval habitat. Metamorphic acceleration was accompanied by increased whole body 3,5,3'-triiodothyronine and hindbrain corticotropin-releasing hormone content by 24 hr after transfer of tadpoles from high to low water. Food restriction for 4 day accelerated metamorphosis and elevated whole body thyroid hormone content. Although tadpoles accelerated metamorphosis and activated their thyroid axis in response to the two environmental manipulations, the kinetics of the responses were greater for water volume reduction than for resource restriction. The modulation of hormone secretion and action by environmental factors provides a mechanistic basis for plasticity in the timing of amphibian metamorphosis, and the neuroendocrine stress axis may play a central role in developmental plasticity.

Postnatal phencyclidine-induced deficit in adult water maze performance is associated with N-methyl-d-aspartate receptor upregulation

The N-methyl-d-aspartate (NMDA) receptor plays an important role in developmental plasticity. Earlier, we have shown that blocking the NMDA receptor with the non-competitive antagonist phencyclidine (PCP), during a brief postnatal period, disrupts the water maze performance in young juvenile rats (starting at 25 days of age). We now show the long-term effects of postnatal phencyclidine exposure on spatial learning and memory. Male and female rats were exposed to PCP (1 and 5mg/kg) or saline, from postnatal days 5–15, and their performance in the Morris water maze (MWM) was tested both as adolescents (starting on postnatal day (PD) 35) and as adults (starting on postnatal day 60). Separate groups of adult male and female postnatal PCP-treated and saline-treated rats were sacrificed and saturation [3H]MK-801 binding experiments were carried out in their hippocampi and frontal cortices; hippocampus and frontal cortex have high densities of NMDA receptors and both regions are important in spatial learning and memory. Postnatal PCP administration disrupted the water maze performance both in adolescent and adult rats of both sexes. Adult male and female rats treated postnatally with PCP had increased maximal [3H]MK-801 binding in the hippocampus and frontal cortex compared to same-sex saline-treated controls. Taken together, repeated postnatal PCP (RPP) administration impaired the acquisition of spatial learning in adolescent and adult male and female rats, and this cognitive deficit was associated with increased [3H]MK-801 labeled NMDA receptor in the hippocampus and frontal cortex. These findings are consistent with the hypothesis that PCP treatment during the postnatal period produces deficits in the water maze performance by disrupting the developing glutamatergic system.

Developmental maturation of the N-methyl-d-aspartic acid receptor channel complex in postnatal rat brain

The N-methyl-d-aspartate (NMDA) receptor plays an important role in developmental plasticity. Previous studies have reported differences between the NMDA receptor-channel complex in the rat pup brain and the adult brain. In the present study, modulation of the NMDA channel complex as a function of age was measured to determine when the temporal switching of the NMDA receptor from the immature form to the adult mature form takes place. [3H]MK-801 binding was measured in the rat forebrain from postnatal day 1 to day 21. Our data suggest the presence of two types of NMDA receptors — an immature type and a mature type. The immature NMDA receptor, seen during the early postnatal period (day 1–day 14) is highly sensitive to spermidine, l-glutamate alone potentiates [3H]MK-801 binding, and glycine failed to potentiate an l-glutamate-induced increase in [3H]MK-801 binding. During the late postnatal period (after day 14) spermidine alone did not increase [3H]MK-801 binding as potently as it did during the early postnatal period, high-affinity [3H]MK-801 binding was not seen in the presence of l-glutamate alone, and l-glutamate and glycine or l-glutamate and spermidine or l-glutamate, glycine and spermidine together, significantly increased [3H]MK-801 binding in a manner similar to that reported in the adult brain. Together, the pharmacology of the NMDA receptor during the early postnatal period differs from the adult-like receptor seen during the late postnatal period, and that in rats the apparent switching of the NMDA receptor from the immature type to the mature type takes place after the second postnatal week.

Cholinergic and noradrenergic afferents influence the functional properties of the postnatal visual cortex in rats.

Based on previous evidence that acetylcholine (ACh) and noradrenaline (NA) play a permissive role in developmental plasticity in the kitten visual cortex, we reinvestigated this topic in the postnatal visual cortex of rats with normal vision. In rats, the functional properties of visual cortical cells develop gradually between the second and the sixth postnatal week (Fagiolini et al., 1994). Cortical cholinergic depletion, by basal forebrain (BF) lesions at postnatal day (PD) 15 (eye opening), leads to a transient disturbance in the distribution of ocular dominance (Siciliano et al., 1997). In the present study, we investigated the development of visual cortical response properties following cytotoxic lesions of the locus coeruleus (LC) alone or in combination with lesions of cholinergic BF. The main result is that early NA depletion impairs the orientation selectivity of cortical neurons, causes a slight increase of their receptive-field size, and reduces the signal-to-noise ratio of cell responses. Similar effects are obtained following NA depletion in adult animals, although the effects of adult noradrenergic deafferentation are significantly more severe than those obtained after early NA depletion. Additional cholinergic depletion causes an additional transient change in ocular-dominance distribution similarly to that obtained after cholinergic deafferentation alone. Comparisons between depletion of NA on the one hand and depletion of both NA and ACh on the other suggest that the effects of combined deafferentation on the functional properties studied result from simple linear addition of the effects of depleting each afferent system alone.

Postnatal phencyclidine treatment differentially regulates N-methyl-D-aspartate receptor subunit mRNA expression in developing rat cerebral cortex.

The present study was designed to determine the effects of chronic neonatal exposure to the NMDA receptor antagonist phencyclidine (PCP) on [3H]MK-801 binding and on gene expression of NMDA receptor subunits in juvenile male rats. Rat pups were injected daily with PCP from day 5 to 15 and killed on day 21. [3H]MK-801 binding was measured by quantitative autoradiography. A sensitive RNase protection assay was employed to determine simultaneously the mRNA levels of NR1 subunit (comprising all different splice variants) and three NR2 subunits (NR2A-NR2C). The relative distribution profile of NMDA receptor subunits in the cerebral cortex was NR2B > NR1 > NR2A > NR2C and in the cerebellum NR2C = NR1 > NR2A = NR2B. Chronic PCP administration in postnatal rats produced significant reduction in both [3H]MK-801 binding and mRNA level of the NR2B subunit in the cerebral cortex. Expression of the other NMDA receptor subunits in the cerebral cortex did not change following the drug treatment. In the cerebellum, neither [3H]MK-801 binding nor any of the NMDA receptor subunit expression levels showed any alteration. Together, these data provide a molecular correlate for chronic postnatal PCP-induced down-regulation of [3H]MK-801 binding in rat cerebral cortex and suggest that the NR2B subunit plays an important role in developmental plasticity.

Involvement of Serotonin in Developmental Plasticity of Kitten Visual Cortex

During a critical period of postnatal development, neuronal connections in the kitten visual cortex are susceptible to experience-dependent modifications. These modifications are facilitated by the neuromodulators noradrenaline and acetylcholine. To address the question of whether serotonin (5-hydroxytryptamine; 5-HT), the other major neuromodulator in the cerebral cortex, also plays a role in developmental plasticity, we investigated whether interference with serotoninergic transmission in the kitten visual cortex affects ocular dominance (OD) plasticity. The serotonin neurotoxin 5,7-dihydroxytryptamine or the serotonin receptor blockers ketanserin and methysergide were infused into the visual cortex of kittens undergoing monocular deprivation. We found that both methods of disrupting serotoninergic transmission reduced OD plasticity. However, to be effective, the receptor blockers ketanserin and methysergide had to be applied in combination, suggesting that coactivation of serotonin receptor subtypes of both the 5-HT1 and 5-HT2 families have a permissive function in OD plasticity. Since activation of 5-HT2 receptors stimulates phosphoinositide hydrolysis, our data suggest that second messengers from the phospholipid pathway may play an important role in developmental plasticity of visual cortex.

Functional N-methyl-D-aspartate receptors develop and persist in heterotopic cortical grafts and regulate expression of transcription factor KROX-24

N-Methyl-D-aspartate (NMDA) receptors are a major subfamily of glutamate receptors and thought to play a pivotal role in developmental plasticity and synaptogenesis, neuronal migration and differentiation. NMDA receptors have also been implicated in neuronal degeneration, as glutamate binding to the receptor initiates rapid excitotoxic signal transduction. Molecular cloning of cDNAs has yielded different NMDA receptor subtypes with an essential NR1 subunit associated with various modulatory NR2 subunits. The NR1 gene is expressed at high levels in virtually all brain structures, but to a distinctly higher extent in cortex than in striatum. Here we report on the development, maintenance and function of glutamate receptors in intrastriatally located cortical grafts. Cortical primordia of rat fetuses (El4) were stereotactically grafted into the rostral striatum of adult recipient rats. Expression of NR1 mRNA was examined by in situ hybridization after post transplantation periods of 2, 6 and 12 months. Analysis of NR1 mRNA expression in grafts after a differentiation period of 2 months revealed equal levels compared to the intact neocortex of the host rats and that of rats with the same ontogenetic age. No downregulation of NR1 mRNA was seen 6 and 12 months after transplantation. To ensure normal function of NMDA receptors in grafts, we studied the effects of a blockade of receptor dependent gene expression, using Krox-24 as a reporter gene. In normal brain tissue, constitutive expression of KROX-24 protein is thought to be maintained by NMDA receptor mediated physiological synaptic activity and can be abolished by the non-competitive NMDA receptor antagonist MK-801. Immunostaining of KROX-24 protein was almost identical in grafts compared to the corresponding neocortex. This constitutive expression of KROX-24 could be abolished by treatment with MK-801. Thus, our data indicate normal development and long term persistence of glutamate receptors with intrinsic excitatory activity in transplants.

Transient increase of NMDA-binding sites in human hippocampus during development

In the human hippocampus, the density of glutamate and N- methyl- d-aspartate (NMDA) binding sites follows during development a bell-shaped curve with a peak at 23–27 fetal weeks. We suggest that there is a transient increased density of NMDA binding sites during a restricted period of hippocampal development; this may play an important role in developmental plasticity.