Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Longitudinally restricted axonal projections of hippocampal granule cells suggest that transverse segments of the granule cell layer may operate independently (the "lamellar" hypothesis). Longitudinal projections of excitatory hilar mossy cells could be viewed as antithetical to lamellar function, but only if longitudinal impulse flow effectively excites distant granule cells. We, therefore, determined the effect of focal granule cell discharges on granule cells located >2 mm along the longitudinal axis. During perforant pathway stimulation in urethane-anesthetized rats, passive diffusion of the GABA(A) receptor antagonist bicuculline methiodide from the tip of a glass recording electrode evoked granule cell discharges and c-Fos expression in granule cells, mossy cells, and inhibitory interneurons, within a approximately 400 microm radius. This focally evoked activity powerfully suppressed distant granule cell-evoked responses recorded simultaneously approximately 2.5-4.5 mm longitudinally. Three days after kainic acid-induced status epilepticus or prolonged perforant pathway stimulation, translamellar inhibition was intact in rats with <40% hilar neuron loss but was consistently abolished after extensive (>85%) hilar cell loss. Retrograde transport of Fluoro-Gold (FG) from the rostral dentate gyrus revealed that few inhibitory interneurons were among the many retrogradely labeled hilar neurons 2.5-4.5 mm longitudinally. Although many somatostatin-positive hilar interneurons effectively transported FG from the distant septum, few of these neurons transported detectable FG from much closer hippocampal injection sites. Inhibitory basket and chandelier cells also exhibited minimal longitudinal FG transport. These findings suggest that translamellar disinhibition may result from the loss of vulnerable, longitudinally projecting mossy cells and may represent a network-level mechanism underlying postinjury hippocampal dysfunction and epileptic network hyperexcitability.
 ...
PMID:Translamellar disinhibition in the rat hippocampal dentate gyrus after seizure-induced degeneration of vulnerable hilar neurons. 1474 30

gamma-Aminobutyric acid (GABA) has been proposed to function as a paracrine signaling molecule in islets of Langerhans. We have shown that rat beta-cells release GABA by Ca(2+)-dependent exocytosis of synaptic-like microvesicles. Here we demonstrate that GABA thus released can diffuse over sufficient distances within the islet interstitium to activate GABA(A) receptors in neighboring cells. Confocal immunocytochemistry revealed the presence of GABA(A) receptors in glucagon-secreting alpha-cells but not in beta- and delta-cells. RT-PCR analysis detected transcripts of alpha(1) and alpha(4) as well as beta(1-3) GABA(A) receptor subunits in purified alpha-cells but not in beta-cells. In whole-cell voltage-clamp recordings, exogenous application of GABA activated Cl(-) currents in alpha-cells. The GABA(A) receptor antagonist SR95531 was used to investigate the effects of endogenous GABA (released from beta-cells) on pancreatic islet hormone secretion. The antagonist increased glucagon secretion at 1 mmol/l glucose twofold and completely abolished the inhibitory action of 20 mmol/l glucose on glucagon release. Basal and glucose-stimulated secretion of insulin and somatostatin were unaffected by SR95531. The L-type Ca(2+) channel blocker isradipine evoked a paradoxical stimulation of glucagon secretion. This effect was not observed in the presence of SR95531, and we therefore conclude that isradipine stimulates glucagon secretion by inhibition of GABA release.
 ...
PMID:Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells. 1504 19

In the present study, we conducted: (i) in situ hybridization in order to investigate the expression of kainate and GABA(A) receptor subunits and the pre-proenkephalin and prodynorphin peptides in the brain of weaver mouse (a genetic model of dopamine deficiency) and (ii) immunocytochemistry in order to study the somatostatin-positive cells in weaver striatum. Our results indicated: (i) increases in mRNA levels of KA2 and GluR6 kainate receptor subunits, of alpha(4) and beta(3) GABA(A) receptor subunits and of pre-proenkephalin and prodynorphin in 6-month-old weaver striatum; (ii) a decrease in alpha(1) and beta(2) GABA(A) subunit mRNAs in 6-month-old weaver globus pallidus; (iii) increases in KA2, alpha(4) and beta(3) and decreases in alpha(2) and beta(2) mRNAs in the 6-month-old weaver somatosensory cortex; and (iv) an increase in somatostatin-immunopositive cells in 3-month-old weaver striatum. We suggest that: (i) in striatum, the alterations are induced by the induction of the transcription factor DeltafosB (for GluR6, pre-proenkephalin and prodynorphin mRNAs) and the suppression of transcription factors like NGF-IB (nerve growth factor inducible B; for the KA2 mRNA), in response to dopamine depletion; (ii) in striatum and cortex, the alterations in the expression of the GABA(A) subunits indicate an increase of extrasynaptic versus a decrease of synaptic GABA(A) receptors; and (iii) in globus pallidus, the increased striatopallidal GABAergic transmission leads to a decrease in the number of GABA(A) receptors. Our results further clarify the regulatory role of dopamine in the expression of amino acid receptors and striatal neuropeptides.
 ...
PMID:Expression of amino acid receptors and neural peptides in the weaver mouse brain. 1662 33

This review summarizes recent developments in the field of sleep regulation, particularly in the role of hormones, and of synthetic GABA(A) receptor agonists. Certain hormones play a specific role in sleep regulation. A reciprocal interaction of the neuropeptides growth hormone (GH)-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) plays a key role in sleep regulation. At least in males GHRH is a common stimulus of non-rapid-eye-movement sleep (NREMS) and GH and inhibits the hypothalamo-pituitary adrenocortical (HPA) hormones, whereas CRH exerts opposite effects. Furthermore CRH may enhance rapid-eye-movement sleep (REMS). Changes in the GHRH:CRH ratio in favor of CRH appear to contribute to sleep EEG and endocrine changes during depression and normal ageing. In women, however, CRH-like effects of GHRH were found. Besides CRH somatostatin impairs sleep, whereas ghrelin, galanin and neuropeptide Y promote sleep. Vasoactive intestinal polypeptide appears to be involved in the temporal organization of human sleep. Beside of peptides, steroids participate in sleep regulation. Cortisol appears to promote REMS. Various neuroactive steroids exert specific effects on sleep. The beneficial effect of estrogen replacement therapy in menopausal women suggests a role of estrogen in sleep regulation. The GABA(A) receptor or GABAergic neurons are involved in the action of many of these hormones. Recently synthetic GABA(A) agonists, particularly gaboxadol and the GABA reuptake inhibitor tiagabine were shown to differ distinctly in their action from allosteric modulators of the GABA(A) receptor like benzodiazepines as they promote slow-wave sleep, decrease wakefulness and do not affect REMS.
 ...
PMID:Neurochemical regulation of sleep. 1677 43

The aim of this study was to determine whether age-associated alterations in the GABAergic input to pyramidal neurons in the hippocampus are due to a dysfunction of GABAergic interneurons, and/or a decrease in their cholinergic control via nicotinic receptors (nAChRs). Electrophysiological recordings were obtained from pyramidal cells in the CA1 area of hippocampal slices from young (3-4 months old) and aged (25-30 months old) Sprague-Dawley rats. Synaptic GABA(A) receptor-mediated inhibitory postsynaptic currents and inhibitory postsynaptic potentials induced by stimulation of the stratum oriens were significantly smaller in aged rats. The frequency (but not amplitude) of spontaneous and miniature GABA inhibitory postsynaptic currents (IPSCs) was reduced in aged rats, suggesting a presynaptic alteration. Tetanic stimulation of cholinergic afferents to release endogenous acetylcholine, or an exogenous application of the nAChR agonist cytisine, increased the frequency of spontaneous IPSCs in young rats; however these effects were not evident in aged rats, indicating that the nicotinic control of GABA release is lowered during aging. None of these age-related alterations were reversed by a chronic treatment with donepezil, a cholinesterase inhibitor. Immunofluorescent labeling of GABA interneurons with somatostatin (SOM), parvalbumin (PV) or calbindin (CB), together with the vesicular acetylcholine transporter VAChT, revealed a selective loss of subpopulations of SOM and CB positive interneurons. This loss was associated with a general decrease in density of the cholinergic network in aged rats. Thus, the lower GABAergic inhibition observed in the aged rat hippocampus is due to a selective loss/dysfunction of subpopulations of GABAergic interneurons, associated with a widespread cholinergic deficit.
 ...
PMID:Age-related alterations of GABAergic input to CA1 pyramidal neurons and its control by nicotinic acetylcholine receptors in rat hippocampus. 1689 Mar 74

Parvalbumin (PV)-expressing interneurons synchronize cortical neurons through gamma-aminobutyric acidergic (GABAergic) synapses. Three types of PV-containing interneurons populate stratum pyramidale of the hippocampal CA1 area: basket cells targeting somata and proximal dendrites, axoaxonic cells innervating axon initial segments, and bistratified cells targeting the dendrites of pyramidal cells. We tested whether this axonal specialization is accompanied by a differential expression of molecules involved in neuronal signaling. Immunofluorescence evaluation of interneurons labeled by neurobiotin in vivo shows that axoaxonic cells express significantly less GABA(A) receptor alpha1 subunit in the plasma membrane than basket and bistratified cells. Electron microscopic immunogold labeling reveals that this subunit contributes heavily to extrasynaptic receptors providing a substrate for tonic inhibition. Results from additional immunofluorescence experiments were consistent with the finding that only bistratified cells express the neuropeptide somatostatin. From the molecular profiles, we estimate that basket, bistratified, and axoaxonic cells represent about 60%, 25%, and 15%, respectively, of PV-containing cells in CA1 stratum pyramidale. In addition, all 3 interneuron classes form connexin36-immunopositive dendrodendritic gap junctions. The differential expression of signaling molecules and the relative frequency of cells reflect the specialized temporal contribution of the 3 types of PV-positive interneurons to GABA release in the network.
 ...
PMID:Immunoreactivity for the GABAA receptor alpha1 subunit, somatostatin and Connexin36 distinguishes axoaxonic, basket, and bistratified interneurons of the rat hippocampus. 1712 64

Neuropeptide Y-containing interneurons in the dentate hilar area play an important role in inhibiting the activity of hippocampal circuitry. Hilar cells are often among the first lost in hippocampal epilepsy. As many types of neurons are found in the hilus, we used a new transgenic mouse expressing green fluorescent protein (GFP) in a subset of neurons that colocalized neuropeptide Y (NPY), somatostatin (SST), and GABA for whole-cell, perforated, and cell-attached recording in 240 neurons. As these neurons have not previously been identifiable in live slices, they have not been the focus of physiological analysis. Hilar NPY neurons showed modest spike frequency adaptation, a large 15.6 +/- 1.0 mV afterhyperpolarization, a mean input resistance of 335 +/- 26 M Omega, and were capable of fast-firing. Muscimol-mediated excitatory actions were found in a nominally Ca(2+)-free/high-Mg(2+) bath solution using cell-attached recording. GABA(A) receptor antagonists inhibited half the recorded neurons and blocked burst firing. Gramicidin perforated-patch recording revealed a GABA reversal potential positive to both the resting membrane potential and spike threshold. Together, these data suggest GABA is excitatory to many NPY cells. NPY and SST consistently hyperpolarized and reduced spike frequency in these neurons. No hyperpolarization of NPY on membrane potential was detected in the presence of tetrodotoxin, AP5, CNQX and bicuculline, supporting an indirect effect. Under similar conditions, SST hyperpolarized the cells, suggesting a direct postsynaptic action. Depolarizing actions of GABA and GABA-dependent burst-firing may synchronize a rapid release of GABA, NPY, and SST, leading to pre- and postsynaptic inhibition of excitatory hippocampal circuits.
 ...
PMID:GABA excitation in mouse hilar neuropeptide Y neurons. 1720 5

In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in gamma-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex- and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD(67)) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA(A) receptor subunits (alpha1, alpha4, beta3, gamma2 and delta). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD(67), SST and alpha1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCK-containing subpopulations of GABA neurons and in the signaling via certain GABA(A) receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.
 ...
PMID:Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. 1747 Dec 87

The majority of hippocampal interneurons strongly express GABA(A) receptors containing the alpha1 subunit, suggesting that inhibitory control of interneurons is important for proper function of hippocampal circuits. Here, we investigated with immunohistochemical and electrophysiological techniques how these GABA(A) receptors are replaced in mice carrying a targeted deletion of the alpha1-subunit gene (alpha1(0/0) mice). Using markers of five major populations of CA1 interneurons (parvalbumin, calretinin, calbindin, neuropeptide Y and somatostatin), we show that these interneurons remain unaffected in alpha1(0/0) mice. In triple immunofluorescence staining experiments combining these markers with the GABA(A) receptor alpha1, alpha2 or alpha3 subunit and gephyrin, we demonstrate a strong increase in alpha3- and alpha2-GABA(A) receptors clustered at postsynaptic sites along with gephyrin in most CA1 interneurons in alpha1(0/0) mice. The changes were cell type-specific and resulted in an increased number of GABAergic synapses on interneurons. These adjustments were mirrored functionally by retention of spontaneous IPSCs with prolonged decay kinetics, as shown by whole-cell patch-clamp recordings of CA1 interneurons. However, a significant decrease in frequency and amplitude of miniature IPSCs was evident, suggesting reduced affinity of postsynaptic receptors and/or impaired vesicular GABA release. Finally, to assess whether these compensatory changes are sufficient to protect against a pathological challenge, we tested the susceptibility of alpha1(0/0) mice against kainic acid-induced excitotoxicity. No genotype difference was observed in the effects of kainic acid, indicating that the absence of a major GABA(A) receptor subtype is functionally compensated for in hippocampal interneurons by a reorganization of inhibitory circuits.
 ...
PMID:Reorganization of GABAergic circuits maintains GABAA receptor-mediated transmission onto CA1 interneurons in alpha1-subunit-null mice. 1755 97

Impairments in cognitive control, such as those involved in working memory, are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC) in individuals with schizophrenia. This dysfunction appears to result, at least in part, from abnormalities in GABA-mediated neurotransmission. In this paper, we review recent findings indicating that the altered DLPFC circuitry in subjects with schizophrenia reflects changes in the expression of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission. Specifically, using a combination of methods, we found that subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding presynaptic regulators of GABA neurotransmission, neuropeptide markers of specific subpopulations of GABA neurons, and certain subunits of the GABA(A) receptor. In particular, alterations in the expression of the neuropeptide somatostatin suggested that GABA neurotransmission is impaired in the Martinotti subset of GABA neurons that target the dendrites of pyramidal cells. In contrast, none of the GABA-related transcripts assessed to date were altered in the DLPFC of monkeys chronically exposed to antipsychotic medications, suggesting that the effects observed in the human studies reflect the disease process and not its treatment. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia may be attributable to altered GABA neurotransmission in specific DLPFC microcircuits.
 ...
PMID:Cell and receptor type-specific alterations in markers of GABA neurotransmission in the prefrontal cortex of subjects with schizophrenia. 1907 29


<< Previous 1 2 3 Next >>