Critical reviews in neurobiology最新文献

Both preclinical and clinical evidence suggested that antidepressant drugs upregulate hippocampal cell proliferation and neurogenesis. In addition, direct evidence was recently published that hippocampal de novo cell proliferation is necessary for antidepressant action. Within this frame, we used primary cultures of rat cerebellar granule cells (CGC) as an in vitro model of central nervous system (CNS) to investigate whether a neurogenic response could be elicited also in the cerebellum, upon chronic treatment with selective serotonin reuptake inhibitors (SSRIs). Furthermore, we assayed the presence of neural precursor cells in CGC, possibly responsive to proliferation and differentiation stimuli. We found that 1 microM fluoxetine increased cell proliferation, as assayed by [3H]-thymidine incorporation. CGC immunocytochemical analysis with neural cell-specific markers revealed the presence of granule neurons, glial cells, and a cell component that we named "round cells." Because only round cells displayed proliferation ability, as revealed by 5-bromo-2'-deoxyuridine (BrdU) labeling, they were further characterized. For this purpose, round cells were isolated and expanded by culturing in a serum-free medium, containing basic fibroblast growth factor (bFGF), before immunocytochemical analysis. We found that round cells were not immunoreactive for glial, neuronal, and oligodendrocyte markers, whereas they were immunoreactive for several immature neuronal markers. Accordingly, round cells could be induced to differentiate into astrocytes, neurons, and oligodendrocytes, either by withdrawing the mitogen bFGF or by exposing them to fluoxetine. These findings suggest that round cells in CGC possess the features and potentials of neural precursors, able to differentiate in mature neural cells upon a pharmacological simulum.

Ionotropic glutamate receptors (iGluRs) mediate the vast majority of fast excitatory synaptic transmissions within the mammalian central nervous system (CNS). As for other ion channel protein families, there has been astounding progress in recent years in elucidating the details of protein structure through the crystallization of at least part of the ion channel protein complex. The result is a new framework for the interpretation of both classic and emerging functional data. Here we summarize, compare, and contrast recent findings for the AMPA, kainate, and NMDA subtypes of glutamate receptor ion channels, with an emphasis on the functional and structural aspects of how agonist binding controls channel gating.

Several lines of evidence indicate that GABA and neuropeptide Y (NPY) are functionally coupled and may interact in the regulation of fear- and anxiety-induced behavior. Neuroanatomical studies demonstrated that GABA and NPY coexist in neurons of the amygdaloid complex and that NPY may directly modulate the activity of GABAergic neurons by stimulating Y1 receptors. By using a transgenic mouse model harboring a construct comprising the murine Y1 receptor gene promoter fused to a lacZ reporter gene (Y1R/LacZ mice), we showed that long-term treatment with positive (diazepam or abecarnil) or negative (FG7142) modulators of GABAA receptor function induced a marked increase or decrease, respectively, in Y1 receptor gene expression in the amygdala. Furthermore, we demonstrated that a sustained increase in the brain concentrations of neuroactive steroids, induced by pharmacological treatment or by physiological conditions such as pregnancy, increases Y1 receptor gene expression in the amygdala of Y1R/LacZ transgenic mice, an effect similar to that induced by diazepam or abecarnil. These data provide evidence of a functional interaction between GABAergic and NPY-Y1 mediated transmission and suggest that neuroactive steroids may play an important role in the regulation of the NPY transmission. Finally, our data support a role of Y1 receptors in the behavioral and neuroendocrine responses to stress that, however, appears to be independent on the activation of the GABAergic system.

Over the last 20 years, great effort has been made to decipher the molecular mechanisms used by cells to transform a cytosolic Ca2+ signal into specific, finely-controlled changes in gene expression. Several previous reviews addressed the variety of regulatory mechanisms that participate in Ca2+ -dependent gene expression in neurons (Carafoli et al., 2001; Mellstrom and Naranjo 2001; West et al., 2001). Nevertheless, recent discoveries have revealed new players and new interactions that tune this process. In this review, we will use the four promoters that regulate the expression of the brain-derived neurotrophic factor (BDNF) gene as a magnificent scenario in which these mechanisms intermingle to show the complexity of Ca2+ -dependent gene expression.

The 5-HT2A serotonin receptor represents the principal molecular target for the actions of both classic hallucinogens, which function as agonists, and atypical antipsychotic drugs, which function as inverse agonists. Pharmacological agents that modify the activity of 5-HT2A receptors are known to modulate human perception and cognition. 5-HT2A receptors are found predominantly in the apical dendritic segment and dendritic spines of cortical pyramidal neurons. This review discusses our current understanding of the molecular and cellular mechanisms governing the preferential targeting of 5-HT2A receptors to apical dendrites and dendritic spines. Uncovering the processes responsible for the polarization of 5-HT2A receptors to neuronal subdomains will likely provide crucial insights into the modulating mechanisms that can affect human cognition and perception.

Activation of protein kinase C (PKC) seems to promote vesicle recruitment to the release-ready state prior to Ca2+ -triggered fusion in chromaffin cells. To understand spatio-temporal regulation of vesicle recruitment by PKC, we studied the effects of a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), on the vesicle movements in living chromaffin cells by imaging with a fluorescence microscope-cooled CCD system. About 60 approximately 80% of the chromaffin vesicles showed a rapid movement, about 20% showed a moderate movement, and the rest showed slow/no movement in resting and post-stimulation. The vesicles with slow/no movement increased to 40% upon a depolarizing stimulation, and TPA increased this population to about 70%. TPA treatment, in addition, increased the number of visible chromaffin vesicles beneath the plasma membrane, suggesting that the potentiation of vesicle recruitment by PKC involves a substantial increase in the subplasmalemmal distribution of vesicles.

Neurosteroids--i.e., steroid produced in brain ex novo or through metabolism of precursors--affect neuronal and brain functions through genomic and nongenomic mechanisms, depending on their molecular structure. Among neurosteroids, 3alpha-hydroxylated, 5alpha-reduced metabolites of progesterone (3alpha-hydroxy,5alpha-pregnan-20one/3alpha,5alpha-THP) and deoxycorticosterone (3alpha,21-dihydroxy,5alpha-pregnan-20one/3alpha,5alpha-THDOC) are positive allosteric modulators of gamma-aminobutyric acid (GABA) action at GABAA receptors. In rodents, a reduction of their endogenous brain concentrations rapidly lowers the potency of GABA in eliciting GABAA receptor-mediated inhibitory postsynaptic currents. This effect is related to anxiety-like behavior, increased aggression, and a reduced sensitivity to the loss of righting reflex induced by GABAA receptor agonist or positive modulators. Conversely, enhancement of 3alpha,5alpha-THP or 3alpha,5alpha-THDOC brain content results in anxiolysis, sedation/hypnosis, anticonvulsant, and anesthetic action. Different classes of psychotropic drugs--i.e., antidepressants, selected atypical antipsychotics, ethanol, gamma-hydroxybutyric acid--increase neurosteroid concentrations in brain, and these increases may be relevant to their pharmacological actions. Drug-induced increases of neurosteroids in rodent brain are often associated with elevation of their plasma content, such that alterations of plasma steroid concentrations are assumed to reflect parallel changes in brain. Nevertheless, brain neurosteroid concentrations are uneven across various regions, and the dose-dependence of their response to a pharmacological challenge shows brain-regional differences as well. These observations are consistent with the present knowledge on the distribution of steroidogenic enzymes in brain--they show not only a brain region, but also a cell-specific expression that may spatially and temporally determine the local concentrations of specific neurosteroids, either produced ex novo or through metabolism of steroid precursors that reach the brain through blood.

Adenosine is an important endogenous purine neuromodulator in the central nervous system that modulates many important cellular processes in neurons. The physiological effects of adenosine are transduced through four pharmacologically classified receptor types i.e., A1, A2A, A2B and A3. All adenosine receptors are G-protein coupled receptors (GPCR) of the type 1 variety. Adaptations in adenosine signaling have been implicated in a wide range of pathophysiological processes, such as epilepsies, sleep disorders, pain, and drug addictions. Knowledge relating to the etiology of addictive processes is far from complete, and as a result the therapeutic options to deal with drug dependence issues are limited. Drugs of abuse mediate their effects through many distinct cellular effectors, such as neurotransmitter transporters, ion channels, and receptor proteins. However, a unifying feature of the major drugs of abuse-i.e., opiates, cocaine, and alcohol-is that they all directly or indirectly modulate adenosine signaling in neurons. Agents targeting adenosine receptors may therefore offer novel avenues for the development of therapies to manage or treat addictions. A consistent cellular adaptation to long-term drug use is the up- or down-regulation of signaling pathways driven by adenylyl cyclase/cyclic AMP (cAMP) in several brain regions linked to addiction. Withdrawal from mu-opioids or cocaine following their chronic administration leads to an upregulation of adenylyl cyclase-mediated signaling, resulting in high levels of cAMP. Cyclic AMP produced in this way acts as a substrate for the endogenous production of adenosine. Increased levels of endogenous adenosine interact with presynaptic A1 receptors to inhibit the excessive neuronal excitation often seen during morphine/cocaine withdrawal. These pre-clinical findings fit well with other data indicating that drugs which boost endogenous adenosine levels or directly interact with inhibitory A1 receptors can alleviate many of the negative consequences of opioid/cocaine withdrawal. Ethanol interacts directly with the adenosine system by blocking nucleoside transporters in the cell membrane. The effect of this inhibition is an increase in extracellular adenosine levels and adenosine receptor activation. Depending on the time course of ethanol exposure and the receptor population present, cAMP levels are either reduced or increased. Chronic ethanol treatment tends to reduce cAMP levels as a consequence of the desensitization of stimulatory GPCRs (such as A2-type receptors) seen following prolonged receptor activation. Unlike opiates and cocaine, adenosine receptor activation worsens the behavioral effects of drug ingestion, and evidence indicates that agents that negatively modulate adenosine receptor function have some utility in attenuating the effects of ethanol use. Taken together, these data suggest that pharmacological manipulation of adenosine signaling represents a potentially useful means of

Inhibitory GABAergic interneurons of prefrontal cortex (PFC) appear to play an important role in the regulation of intermittent pyramidal neuron columnary firing and in the neuronal plasticity that mediate cognitive functions. In schizophrenia (SZ), cognitive defects and dysfunctions in pyramidal neuronal columnary firing appear to depend on abnormalities of GABAergic neurons. These abnormalities include a decrease of GAD67 and reelin expression, which result in a reduction of cortical inhibitory input to spine postsynaptic densities as a result of the decrease of GABA concentration at the synaptic cleft, and of neurotrophic stimuli as a result of the decrease of reelin secreted into the extracellular matrix. Our studies show that alterations in chromatin remodeling related to a selective upregulation of DNA-5-cytosine methyltransferase (DNMT) expression in GABAergic neurons of SZ PFC may induce a hypermethylation of reelin and GAD67 promoter CpG islands, which downregulates their expression. In addition, we report preliminary evidence suggesting that by targeting this chromatin-remodeling deficit with inhibitors of histone deacetylases (HDAC), it may be possible to reduce the DNMT upregulation via a covalent modification of nucleosomal histone tails, underscoring the possibility that by addressing a chromatin remodeling deficit, one may treat psychiatric disorders.