[Abstract unavailable

Endoplasmic reticulum (ER) stress is caused by disturbances in the structure and function of the ER with the accumulation of misfolded proteins and alterations in the calcium homeostasis. The ER response is characterized by changes in specific proteins, causing translational attenuation, induction of ER chaperones and degradation of misfolded proteins.

The mRNAs of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) exhibit a similar, though not identical, regional and cellular distribution in the rodent brain. In situ hybridization experiments have shown that BDNF, like NGF, is predominantly expressed by neurons. The neuronal localization of the mRNAs of these two neurotrophic molecules raised the question as to whether neuronal activity might be involved in the regulation of their synthesis. After we had demonstrated that depolarization with high potassium (50 mM) resulted in an increase in the levels of both BDNF and NGF mRNAs in cultures of hippocampal neurons, we investigated the effect of a large number of transmitter substances. Kainic acid, a glutamate receptor agonist, was by far the most effective in increasing BDNF and NGF mRNA levels in the neurons, but neither N‐methyl‐D‐aspartic acid (NMDA) nor inhibitors of the NMDA glutamate receptors had any effect. However, the kainic acid mediated increase was blocked by antagonists of non‐NMDA receptors. Kainic acid also elevated levels of BDNF and NGF mRNAs in rat hippocampus and cortex in vivo. These results suggest that the synthesis of these two neurotrophic factors in the brain is regulated by neuronal activity via non‐NMDA glutamate receptors.

The Schwann cells and fibroblast-like cells of the intact sciatic nerve of adult rats synthesize very little nerve growth factor (NGF). After lesion, however, there is a dramatic increase in the amounts of both NGF-mRNA and NGF protein synthesized by the sciatic non-neuronal cells. This local increase in NGF synthesis partially replaces the interrupted NGF supply from the periphery to the NGF-responsive sensory and sympathetic neurons, whose axons run within the sciatic nerve. Macrophages, known to invade the site of nerve lesion during wallerian degeneration, are important in the regulation of NGF synthesis. Here we demonstrate that the effect of macrophages on NGF-mRNA levels in cultured explants of sciatic nerve can be mimicked by conditioned media of activated macrophages, and that interleukin-1 is the responsible agent.

STRACTIn newborn rats the levels of nerve growth fa tor (NGF) mRNA (mRNANGF) and NGF receptor mRNA ( A') in the sciatic nerve were 10 and 120 times higher, r pectively, than in adult animals. mRNAL levels decreased st adily from birth, approaching adult levels by the third stnatal week, whereas mRNANUF levels decreased only after th first postnatal week, although also reaching adult levels by the third week. Transection of the adult sciatic nerve resulted in a marked biphasic increase in mRNANGF with time. On the p oximal side of the cut, this increase was confined to the area immediately adjacent to the cut; peripherally, a similar biphasic increase was present in all segments. mRNAL levels were al markedly elevated distal to the transection site, in agreem nt with previous results obtained by immunological transection of the sciatic nerve, local NGF synthesis increases dramatically. Augmented NGF synthesis is observed in all segments distal to the transection site but is confined proximally to those parts of the nerve stump immediately adjacent to the lesion (9). This part of the nerve stump may be considered as a "substitute target" for the axotomized and then regenerating axons of the sympathetic and sensory neurons. Although the NGF concentrations in the proximal nerve stump correspond to those of a densely innervated peripheral target organ (10, 11), the volume ofthe "substitute organ" is too small to fully replace the interrupted supply from the peripheral physiological target tissues. This is apparent from the fact that the NGF levels in the proximal unlesioned part of the sciatic nerve reach only 40% of their normal values (9). Simultaneously with the enhanced synthesis of NGF, the transection of the sciatic nerve leads also to reexpression of NGF receptors by Schwann cells (12), receptors normally seen only in earlier stages of development (13,14).In the present study we asked whether the reexpression of NGF receptors and the enhanced synthesis of NGF by Schwann cells are mediated by a common mechanism. We first followed the developmental changes in the levels of mRNA encoding NGF (mRNANGF) and of mRNA encoding NGF receptor (mRNArec) from birth to adulthood and then compared the time course of the levels of these two mRNAs after sciatic nerve transection both distally and proximally to the lesion. In experiments using a crush injury rather than transection, we studied whether neuronal regeneration brought about the return of mRNANGF and mRNA1 to normal levels. MATERIALS AND METHODSPreparation of Sciatic Nerves. Wistar rats (male or female, 150-200 g) were anesthetized with diethyl ether and the sciatic nerve was cut or crushed at the sciatic notch. After cutting, the distal stump of the nerve was diverted into muscle tissue in order to minimize regrowth of fibers. For crushing of the nerve, forceps were cooled in liquid nitrogen and the crush site was marked by a thread.At various times after nerve injury, animals were killed, the nerves were cut into three segments [B (proximal)

In the central nervous system brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are predominantly located in neurons. Here we demonstrate that the balance between the activity of the glutamatergic and y-aminobutyric acid (GABA)ergic systems controls the physiological levels of BDNF and NGF mRNAs in hippocampal neurons in vitro and in vivo. The blockade of the glutamate receptors and/or stimulation of the GABAergic system reduces BDNF and NGF mRNAs in hippocampus and NGF protein in hippocampus and septum. The reduction of NGF in the septum reflects the diminished availability of NGF in the projection field of NGF-dependent septal cholinergic neurons. These neurons do not synthesize NGF themselves but accumulate it by retrograde axonal transport. The refined and rapid regulation of BDNF and NGF synthesis by the glutamate and GABA transmitter systems suggests that BDNF and NGF might be involved in activity-dependent synaptic plasticity.Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are two structurally related neurotrophic molecules (1), which are expressed by specific populations of central neurons including pyramidal neurons in the hippocampus proper and granular neurons of the dentate gyrus (2-8). NGF is produced in the hippocampus and is specifically taken up by nerve terminals of cholinergic neurons. The cell bodies of these neurons are localized in the septum, and they accumulate NGF by retrograde axonal transport (9). NGF (10-12) and probably also BDNF (13,14) promote the survival and maintenance of specialized functions of these septal cholinergic neurons.Glutamate is the major excitatory neurotransmitter in the mammalian brain, whereas y-aminobutyric acid (GABA) mediates the main inhibitory input on neurons. The appropriate balance between the effects of these neurotransmitter systems appears essential for normal neuronal function, and deviations from this balance may lead to seizures and neuronal cell death (15,16). lonotropic glutamate receptors can, according to pharmacological criteria, be divided into N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors, which include kainate and a-amino-3-hydroxymethylisoxazole4propion-ate (AMPA) receptors (17). The normal and pathophysiological functions of these receptors are particularly well studied in the hippocampus. The activation of NMDA receptors, for example, seems to play a critical role in long-term potentiation (18, 19), whereas uncontrolled hippocampal glutamatereceptor activation leads to seizures and irreversible neuronal damage (15, 16).We have previously shown that depolarization of cultured hippocampal neurons (50 mM KCl) increases both BDNF and NGF mRNA levels in a calcium-dependent manner (20). Of a large number of transmitter substances tested, kainic acid proved the most potent molecule in elevating BDNF and NGF mRNAs in vitro and in vivo (20). However, the use of pharmacological doses of kainic acid (20,21) or the induction of limbic seizures (22) represents extreme experimental cond...

No abstract

Specific sensory input has profound transient and long-lasting effects on the function of corresponding sensory cortical areas both during development and in adulthood. To study whether neurotrophic factors might play a role in such processes, we investigated the effects of light on the nerve growth factor and brain-derived neurotrophic factor (BDNF) mRNA levels in rat visual cortex. Keeping adult rats in the dark or preventing normal activity of retinal ganglion cells by intraocular injection of tetrodotoxin significantly decreased the levels of BDNF mRNA in the visual cortex but not in other cortical areas. Exposure to light after a period in darkness rapidly restored the mRNA to control levels. These alterations in visual input had no effect on nerve growth factor mRNA. The mRNA of trkB, the putative signal-transducing receptor unit for BDNF, was also decreased in darkness, although less than BDNF mRNA. BDNF mRNA levels increased in the visual cortex of newborn rats after eye-opening. This increase is retarded, although not completely abolished, by rearing the pups in darkness. Thus, the levels of BDNF mRNA are rapidly regulated by sensory input during development and in adulthood. BDNF may therefore play an important role in formation and in activity-dependent modulation of specific connections in the visual cortex.Visual input has profound influences on neuronal connectivity in the visual cortex. During a critical period of development, receptive fields in the visual cortex are determined in a use-dependent competition between the two eyes (1, 2). Although the neuronal connections in adult visual cortex were previously thought to be fairly stable, recent experiments indicate that alterations in sensory input have rapid and marked effects on functional and structural connectivity in the adult sensory cortex (3, 4). The activation of N-methyl-D-aspartate (NMDA)-type glutamate receptors is thought to play an essential role in these use-dependent changes (5). However, the mechanisms through which NMDA receptor activation leads to alterations in the neuronal connectivity are poorly understood.Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), two members of the neurotrophin gene family, are predominantly synthesized by neurons in the central nervous system (6-17). Neuronal activity has been shown to regulate the mRNAs for NGF and BDNF in the hippocampus (18)(19)(20). The basal expression of these two neurotrophins in hippocampal neurons seems to be predominantly determined by the balance between glutamatergic and GABAergic transmitter systems (19). The rapid and subtle activity-dependent regulation of synthesis of these two neurotrophins suggests that, in addition to supporting the survival and regulation of specific neuronal properties, these neurotrophins may also act as mediators of functional and structural changes in neuronal connectivity. We have investigated here whether changes in visual input regulate the expression of NGF and BDNF mRNA in the visual cortex during developmen...