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1.
Neuropeptides ; 61: 49-55, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27847128

ABSTRACT

Neuropeptide Y (NPY)-Y2 receptors are G-protein coupled receptors and, upon activation, induce opening of potassium channels or closing of calcium channels. They are generally presynaptically located. Depending on the neuron in which they are expressed they mediate inhibition of release of NPY and of the neuron's classical transmitter GABA, glutamate or noradrenaline, respectively. Here we provide evidence that Y2 receptor binding is inhibited dose-dependently by GTPγS along Schaffer collaterals, the stria terminalis and the fimbria indicating that Y2 receptors are functionally coupled to G-proteins along these fiber tracts. Double immune fluorescence revealed coexistence of Y2-immunoreactivity with ß-tubulin, a marker for axons in the stria terminalis, but not with synaptophysin labeling presynaptic terminals, supporting the localization of Y2 receptors along axonal tracts. After kainic acid-induced seizures in rats, GTPγS-induced inhibition of Y2 receptor binding is facilitated in the Schaffer collaterals but not in the stria terminalis. Our data indicate that Y2 receptors are not only located at nerve terminals but also along fiber tracts and are there functionally coupled to G-proteins.


Subject(s)
Axons/metabolism , GTP-Binding Proteins/metabolism , Nerve Fibers/metabolism , Neurons/metabolism , Receptors, Neuropeptide Y/metabolism , Seizures/metabolism , Animals , Hippocampus/metabolism , Kainic Acid , Male , Rats , Rats, Sprague-Dawley , Seizures/chemically induced , Synaptophysin/metabolism , Tubulin/metabolism
2.
Adv Exp Med Biol ; 548: 92-103, 2004.
Article in English | MEDLINE | ID: mdl-15250588

ABSTRACT

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain. It acts through 2 classes of receptors, GABAA receptors that are ligand-operated ion channels and the G-protein-coupled metabotropic GABAB receptors. Impairment of GABAergic transmission by genetic mutations or application of GABA receptor antagonists induces epileptic seizures, whereas drugs augmenting GABAergic transmission are used for antiepileptic therapy. In animal epilepsy models and in tissue from patients with temporal lobe epilepsy, loss in subsets of hippocampal GABA neurons is observed. On the other hand, electrophysiological and neurochemical studies indicate a compensatory increase in GABAergic transmission at certain synapses. Also, at the level of the GABAA receptor, neurodegeneration-induced loss in receptors is accompanied by markedly altered expression of receptor subunits in the dentate gyrus and other parts of the hippocampal formation, indicating altered physiology and pharmacology of GABAA receptors. Such mechanisms may be highly relevant for seizure induction, augmentation of endogenous protective mechanisms, and resistance to antiepileptic drug therapy. Other studies suggest a role of GABAB receptors in absence seizures. Presynaptic GABAB receptors suppress neurotransmitter release. Depending on whether this action is exerted in GABAergic or glutamatergic neurons, there may be anticonvulsant or proconvulsant actions.


Subject(s)
Brain Chemistry/physiology , Epilepsy/physiopathology , Receptors, GABA/physiology , gamma-Aminobutyric Acid/physiology , Animals , Humans
3.
Hippocampus ; 13(7): 806-15, 2003.
Article in English | MEDLINE | ID: mdl-14620876

ABSTRACT

Kainic acid-induced seizures cause a marked increase in the expression of glutamate decarboxylase 67 (GAD67) in granule cells of the dentate gyrus. To determine the possible modes of sequestration of newly formed gamma-aminobutyric acid (GABA), we used in situ hybridization and immunocytochemistry to investigate the expression of several proteins related to GABA in dentate granule cells of rats 4 h to 60 days after kainic acid-induced status epilepticus and in controls. GAD67 and GAD65 mRNA levels were increased by up to 300% and 800%, respectively, in the granule cell layer 6-24 h after kainate injection. Subsequently, increased GAD and GABA immunoreactivity was observed in the terminal field of mossy fibers and in presumed dendrites of granule cells. mRNA of both known plasma membrane GABA transporters (GAT-1 and GAT-3) was expressed in granule cells of control rats. GAT-1 mRNA levels increased (by 30%) 9 h after kainate injection but were reduced by about 25% at later intervals. GAT-3 mRNA was reduced (by 35-75%) in granule cells 4 h to 30 days after kainic acid injection. In contrast, no expression of the mRNA or immunoreactivity of the vesicular GABA transporter was detected in granule cells or in mossy fibers, respectively. GABA transaminase mRNA was only faintly expressed in granule cells, and its levels were reduced (by 60-65%) 12 h to 30 days after kainate treatment. The results indicate that GABA can be taken up and synthesized in granule cells. No evidence for the expression of the vesicular GABA transporter (VGAT) in granule cells was obtained. After sustained epileptic seizures, the markedly increased expression of glutamate decarboxylase and the reduced expression of GABA transaminase may result in increased cytoplasmic GABA concentrations in granule cells. It is suggested that, during epileptic seizures, elevated intracellular GABA and sodium concentration could then result in nonvesicular release of GABA from granule cell dendrites. GABA could then act on GABA-A receptors, protecting granule cells from overexcitation.


Subject(s)
Carrier Proteins/metabolism , Cell Membrane/metabolism , Dentate Gyrus/metabolism , Epilepsy, Temporal Lobe/metabolism , Epilepsy/metabolism , Membrane Proteins/metabolism , Neurons/metabolism , Organic Anion Transporters , Animals , Dentate Gyrus/physiopathology , Disease Models, Animal , Epilepsy/chemically induced , Epilepsy/genetics , Epilepsy/physiopathology , Epilepsy, Temporal Lobe/genetics , Epilepsy, Temporal Lobe/physiopathology , GABA Plasma Membrane Transport Proteins , Glutamate Decarboxylase/genetics , Isoenzymes/genetics , Kainic Acid/pharmacology , Male , Membrane Transport Proteins/genetics , Mossy Fibers, Hippocampal/enzymology , Mossy Fibers, Hippocampal/physiopathology , Neurons/cytology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Up-Regulation/drug effects , Up-Regulation/genetics , gamma-Aminobutyric Acid/biosynthesis
4.
Neurosci Lett ; 352(2): 141-5, 2003 Dec 04.
Article in English | MEDLINE | ID: mdl-14625043

ABSTRACT

Malfunctioning of the GABA-ergic system has been postulated as a possible cause of epilepsy. We investigated changes in the mRNA expression of the GABA(B) receptor subtypes GABA(B)-R1 and GABA(B)-R2 and of GABA(B) receptor binding in the hippocampus of patients with temporal lobe epilepsy (TLE) compared with post-mortem controls. In patients with Ammon's horn sclerosis, significant decreases in [3H]CG54626A binding were observed in subfields CA1 and CA3 of the hippocampus proper and the dentate hilus. On the other hand, both GABA(B) receptor mRNAs and receptor binding were enhanced after correction for neuronal loss in dentate granule cells and in the molecular layer, respectively, and the subiculum of patients with and without hippocampal sclerosis. These increases were even more pronounced when correcting the values for cell losses in the respective areas and indicated also increased expression of GABA(B)-R in the dentate hilus. Increased expression of both subtypes of GABA(B) receptors indicates augmented presynaptic inhibition of glutamate release as a possible protective mechanism in TLE.


Subject(s)
Epilepsy, Temporal Lobe/metabolism , Gene Expression Regulation/physiology , Hippocampus/metabolism , Receptors, GABA-B/biosynthesis , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Epilepsy, Temporal Lobe/genetics , Epilepsy, Temporal Lobe/pathology , Hippocampus/pathology , Humans , Middle Aged , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, GABA-B/genetics
5.
J Neuropathol Exp Neurol ; 62(8): 820-34, 2003 Aug.
Article in English | MEDLINE | ID: mdl-14503638

ABSTRACT

It has been postulated that dysfunction of the GABA-ergic transmission is causatively related to the development of epilepsy. Animal models of temporal lobe epilepsy (TLE) revealed considerable changes in the expression of GABA(A) receptor subunits in the hippocampus. Using immunocytochemistry, we investigated the expression of GABA(A) receptor subunits alpha1, alpha3, beta1-3, and gamma2 in hippocampal specimens obtained at surgery from TLE patients with and without hippocampal sclerosis and in autopsy controls. Consistent with the severe neurodegeneration in the CA1 sector, significant decreases in alpha1-, alpha3-, beta3-, and gamma2-subunit immunoreactivity (IR) were detected in sclerotic but not in nonsclerosic specimens. In contrast, pronounced increases in IR of all 3 beta-subunits were observed in most sectors of the hippocampal formation both in sclerotic and nonsclerotic specimens, being especially pronounced in the dentate molecular layer and in the subiculum where subunit alpha3- and gamma2-IR were also elevated. Using in situ hybridization for subunits beta2 and beta3, increased expression of the respective mRNAs was detected in dentate granule cells of patients with and without hippocampal sclerosis. Beta-subunits are important constituents of the GABA(A) receptor and contribute to the binding site of GABA. Our data indicate pronounced adaptive changes in the expression of these GABA(A) receptor subunits related to seizure activity and indicate altered assembly of GABA(A) receptors in TLE.


Subject(s)
Epilepsy, Temporal Lobe/metabolism , Epilepsy, Temporal Lobe/pathology , Hippocampus/metabolism , Receptors, GABA-A/metabolism , Adolescent , Adult , Blotting, Western/methods , Cell Count/methods , Child, Preschool , Densitometry/instrumentation , Densitometry/methods , Epilepsy, Temporal Lobe/genetics , Female , Humans , Immunohistochemistry/methods , In Situ Hybridization/methods , Male , Middle Aged , Phosphopyruvate Hydratase/metabolism , Protein Subunits/genetics , Protein Subunits/metabolism , Receptors, GABA-A/genetics , Sclerosis/etiology , Sclerosis/metabolism , Sclerosis/pathology
6.
Brain Res Mol Brain Res ; 113(1-2): 107-15, 2003 May 12.
Article in English | MEDLINE | ID: mdl-12750012

ABSTRACT

Epilepsy is closely related to an altered transmission of GABA, the major inhibitory transmitter in the brain. GABA acts through two classes of receptors, ionotropic GABA(A) receptors and metabotropic GABA(B) receptors. Using in situ hybridization, receptor autoradiography and immunocytochemistry, we now investigated temporal changes in the expression the GABA(B)-1 and GABA(B)-2 subunits (GABA(B)-1R and GABA(B)-1R, respectively) in the hippocampus following kainic-acid-induced seizures. Significant decreases (by about 40%) in mRNA levels of both splice variants (a and b) of GABA(B)-1R and of GABA(B)-2R were observed in the principal cell layer of the hippocampus 6-12 h after kainic acid injection in the rat. Whereas mRNA levels in the granule cell layer returned to basal after 24 h, the decreases persisted in sectors CA1 and CA3, presumably due to progressing neurodegeneration. In the sector CA3, GABA(B)-R mRNA levels and GABA(B)-R1 immunoreactivity partially recovered 30 days after the initial kainic acid seizures indicating receptor upregulation in surviving neurons.


Subject(s)
Epilepsy/metabolism , Hippocampus/metabolism , Neural Pathways/drug effects , Neurons/drug effects , Receptors, GABA-B/metabolism , Animals , Dentate Gyrus/drug effects , Dentate Gyrus/metabolism , Dentate Gyrus/physiopathology , Down-Regulation/drug effects , Down-Regulation/genetics , Epilepsy/chemically induced , Epilepsy/physiopathology , Excitatory Amino Acid Agonists/pharmacology , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Hippocampus/drug effects , Hippocampus/physiopathology , Kainic Acid/pharmacology , Male , Nerve Degeneration/chemically induced , Nerve Degeneration/genetics , Nerve Degeneration/metabolism , Neural Inhibition/drug effects , Neural Inhibition/physiology , Neural Pathways/metabolism , Neural Pathways/physiopathology , Neurons/metabolism , Protein Subunits/drug effects , Protein Subunits/genetics , Protein Subunits/metabolism , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, GABA-B/drug effects , Receptors, GABA-B/genetics , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Up-Regulation/drug effects , Up-Regulation/physiology , gamma-Aminobutyric Acid/metabolism
8.
Proc Natl Acad Sci U S A ; 99(13): 8938-43, 2002 Jun 25.
Article in English | MEDLINE | ID: mdl-12072562

ABSTRACT

Neuropeptide Y is implicated in energy homeostasis, and contributes to obesity when hypothalamic levels remain chronically elevated. To investigate the specific role of hypothalamic Y2 receptors in this process, we used a conditional Y2 knockout model, using the Cre-lox system and adenoviral delivery of Cre-recombinase. Hypothalamus-specific Y2-deleted mice showed a significant decrease in body weight and a significant increase in food intake that was associated with increased mRNA levels for the orexigenic NPY and AgRP, as well as the anorexic proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the arcuate nucleus. These hypothalamic changes persisted until at least 34 days after Y2 deletion, yet the effect on body weight and food intake subsided within this time. Plasma concentrations of pancreatic polypeptide and corticosterone were 3- to 5-fold increased in hypothalamus-specific Y2 knockout mice. Germ-line Y2 receptor knockout also produced a significant increase in plasma levels of pancreatic polypeptide. However, these mice differed from conditional knockout mice in that they showed a sustained reduction in body weight and adiposity associated with increased NPY and AgRP but decreased POMC and CART mRNA levels in the arcuate nucleus. The transience of the observed effects on food intake and body weight in the hypothalamus-specific Y2 knockout mice, and the difference of this model from germ-line Y2 knockout mice, underline the importance of conditional models of gene deletion, because developmental, secondary, or extrahypothalamic mechanisms may mask such effects in germ-line knockouts.


Subject(s)
Body Weight , Hypothalamus/physiology , Receptors, Neuropeptide Y/physiology , Animals , Base Sequence , Corticosterone/blood , DNA Primers , Feeding Behavior , Gene Deletion , Germ Cells , In Situ Hybridization , Mice , Mice, Knockout , Pancreatic Polypeptide/blood , Receptors, Neuropeptide Y/genetics
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