@article{MTMT:2755870, title = {Abeta(1-42) Enhances Neuronal Excitability in the CA1 via NR2B Subunit-Containing NMDA Receptors}, url = {https://m2.mtmt.hu/api/publication/2755870}, author = {Varga, Edina and Juhász, Gábor and Bozsó, Zsolt and Penke, Botond and Fülöp, Lívia and Szegedi, Viktor}, doi = {10.1155/2014/584314}, journal-iso = {NEURAL PLAST}, journal = {NEURAL PLASTICITY}, volume = {2014}, unique-id = {2755870}, issn = {2090-5904}, abstract = {Neuronal hyperexcitability is a phenomenon associated with early Alzheimer's disease. The underlying mechanism is considered to involve excessive activation of glutamate receptors; however, the exact molecular pathway remains to be determined. Extracellular recording from the CA1 of hippocampal slices is a long-standing standard for a range of studies both in basic research and in neuropharmacology. Evoked field potentials (fEPSPs) are regarded as the input, while spiking rate is regarded as the output of the neuronal network; however, the relationship between these two phenomena is not fully clear. We investigated the relationship between spontaneous spiking and evoked fEPSPs using mouse hippocampal slices. Blocking AMPA receptors (AMPARs) with CNQX abolished fEPSPs, but left firing rate unchanged. NMDA receptor (NMDAR) blockade with MK801 decreased neuronal spiking dose dependently without altering fEPSPs. Activating NMDARs by small concentration of NMDA induced a trend of increased firing. These results suggest that fEPSPs are mediated by synaptic activation of AMPARs, while spontaneous firing is regulated by the activation of extrasynaptic NMDARs. Synaptotoxic Abeta(1-42) increased firing activity without modifying evoked fEPSPs. This hyperexcitation was prevented by ifenprodil, an antagonist of the NR2B NMDARs. Overall, these results suggest that Abeta(1-42) induced neuronal overactivity is not dependent on AMPARs but requires NR2B.}, year = {2014}, eissn = {1687-5443}, orcid-numbers = {Bozsó, Zsolt/0000-0002-5713-3096; Penke, Botond/0000-0003-0938-0567; Fülöp, Lívia/0000-0002-8010-0129; Szegedi, Viktor/0000-0003-4191-379X} } @article{MTMT:109992, title = {Relationship between neuronal vulnerability and potassium-chloride cotransporter 2 immunoreactivity in hippocampus following transient forebrain ischemia}, url = {https://m2.mtmt.hu/api/publication/109992}, author = {Papp, Edit and Rivera, C and Kaila, K and Freund, Tamás}, doi = {10.1016/j.neuroscience.2008.03.072}, journal-iso = {NEUROSCIENCE}, journal = {NEUROSCIENCE}, volume = {154}, unique-id = {109992}, issn = {0306-4522}, abstract = {Cation chloride cotransporters have been reported to be expressed in neurons in the hippocampus and to regulate intracellular Cl(-) concentration. The neuron-specific K-Cl cotransporter 2 (KCC2) is necessary for maintaining the low intracellular chloride concentration required for the hyperpolarizing actions of GABA. In this study we examined the vulnerability of KCC2-containing neurons as well as the changes in the pattern of KCC2 distribution in the rat hippocampus following 15 min ischemia induced by four-vessel occlusion. Immunostaining for the 72 kDa heat shock protein (HSP-72) was used to investigate the extent of damage in neuronal populations previously shown to be vulnerable to ischemia. At 6-24 h after ischemia, when the pyramidal cells in the CA1 (subfield of cornu Ammonis) region showed no morphological signs of damage, a small rise of KCC2 immunoreactivity was already observed. After 2 days, when the CA1 pyramidal cells started to degenerate, a progressive downregulation of the KCC2 protein was visible. Interestingly, in the same areas, the parvalbumin containing interneurons showed no signs of ischemic damage, and KCC2 immunoreactivity was retained on their membrane surface. In CA1 pyramidal cells, the reduction in KCC2 expression may lead to an elevation of intracellular Cl(-) concentration, which causes a shift in equilibrium potential toward more positive levels. Consequently, the reduction of the inhibitory action of GABA through downregulation of KCC2 function may be involved in the pathomechanisms of delayed neuronal death in the CA1 subfield.}, year = {2008}, eissn = {1873-7544}, pages = {677-689} } @article{MTMT:2287575, title = {Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2.}, url = {https://m2.mtmt.hu/api/publication/2287575}, author = {Rivera, C and Voipio, J and Thomas-Crusells, J and Li, H and Emri, Zsuzsa and Sipila, S and Payne, JA and Minichiello, L and Saarma, M and Kaila, K}, doi = {10.1523/JNEUROSCI.5265-03.2004}, journal-iso = {J NEUROSCI}, journal = {JOURNAL OF NEUROSCIENCE}, volume = {24}, unique-id = {2287575}, issn = {0270-6474}, abstract = {GABA-mediated fast-hyperpolarizing inhibition depends on extrusion of chloride by the neuron-specific K-Cl cotransporter, KCC2. Here we show that sustained interictal-like activity in hippocampal slices downregulates KCC2 mRNA and protein expression in CA1 pyramidal neurons, which leads to a reduced capacity for neuronal Cl- extrusion. This effect is mediated by endogenous BDNF acting on tyrosine receptor kinase B (TrkB), with down-stream cascades involving both Shc/FRS-2 (src homology 2 domain containing transforming protein/FGF receptor substrate 2) and PLCgamma (phospholipase Cgamma)-cAMP response element-binding protein signaling. The plasmalemmal KCC2 has a very high rate of turnover, with a time frame that suggests a novel role for changes in KCC2 expression in diverse manifestations of neuronal plasticity. A downregulation of KCC2 may be a general early response involved in various kinds of neuronal trauma.}, keywords = {Animals; MICE; RATS; Cell Membrane/metabolism; Rats, Wistar; RNA, Messenger/metabolism; Chlorides/metabolism; Synaptic Transmission/physiology; Phosphorylation/drug effects; Cyclic AMP Response Element-Binding Protein/metabolism; Signal Transduction/physiology; Pyramidal Cells/metabolism; *Adaptor Proteins, Signal Transducing; Magnesium/pharmacology; Neurons/drug effects/*metabolism; Type C Phospholipases/metabolism; Mice, Mutant Strains; Biotinylation; Phospholipase C gamma; Shc Signaling Adaptor Proteins; Binding Sites/physiology; Hippocampus/cytology/physiology; Symporters/genetics/*metabolism; Receptor, trkB/drug effects/genetics/metabolism; Down-Regulation/drug effects/*physiology; Brain-Derived Neurotrophic Factor/pharmacology/physiology; Adaptor Proteins, Vesicular Transport/metabolism}, year = {2004}, eissn = {1529-2401}, pages = {4683-4691} } @article{MTMT:3301448, title = {Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain.}, url = {https://m2.mtmt.hu/api/publication/3301448}, author = {Coull, JA and Boudreau, D and Bachand, K and Prescott, SA and Nault, F and Sík, Attila and De Koninck, P and De Koninck, Y}, doi = {10.1038/nature01868}, journal-iso = {NATURE}, journal = {NATURE}, volume = {424}, unique-id = {3301448}, issn = {0028-0836}, abstract = {Modern pain-control theory predicts that a loss of inhibition (disinhibition) in the dorsal horn of the spinal cord is a crucial substrate for chronic pain syndromes. However, the nature of the mechanisms that underlie such disinhibition has remained controversial. Here we present evidence for a novel mechanism of disinhibition following peripheral nerve injury. It involves a trans-synaptic reduction in the expression of the potassium-chloride exporter KCC2, and the consequent disruption of anion homeostasis in neurons of lamina I of the superficial dorsal horn, one of the main spinal nociceptive output pathways. In our experiments, the resulting shift in the transmembrane anion gradient caused normally inhibitory anionic synaptic currents to be excitatory, substantially driving up the net excitability of lamina I neurons. Local blockade or knock-down of the spinal KCC2 exporter in intact rats markedly reduced the nociceptive threshold, confirming that the reported disruption of anion homeostasis in lamina I neurons was sufficient to cause neuropathic pain.}, keywords = {Animals; Male; RATS; Chronic Disease; Models, Neurological; pain threshold; Receptors, GABA-A/metabolism; Homeostasis; Synapses/*metabolism; Neurons/*metabolism; Pain/*physiopathology; Anions/metabolism; Peripheral Nerves/physiopathology; Peripheral Nerve Injuries; In Vitro Techniques; Symporters/antagonists & inhibitors/genetics/*metabolism; Spinal Cord/*cytology/*physiopathology; Receptors, Glycine/metabolism}, year = {2003}, eissn = {1476-4687}, pages = {938-942} } @article{MTMT:108650, title = {Increased number of synaptic GABA~A receptors underlies potentiation at hippocampal inhibitory synapses}, url = {https://m2.mtmt.hu/api/publication/108650}, author = {Nusser, Zoltán and Hájos, Norbert and Somogyi, Péter Pál and Mody, I}, doi = {10.1038/25999}, journal-iso = {NATURE}, journal = {NATURE}, volume = {395}, unique-id = {108650}, issn = {0028-0836}, abstract = {Changes in synaptic efficacy are essential far neuronal development(1), learning and memory formation(2) and for pathological slates of neuronal excitability, including temporal-lobe epilepsy(3), At synapses, where there is a high probability of opening of postsynaptic receptors(4), all of which are occupied by the released transmitter(5-9), the most effective means of augmenting postsynaptic responses is to increase the number of receptors(2,10,11). Here we combine quantal analysis of evoked inhibitory postsynaptic currents with quantitative immunogold localization of synaptic GABA(A) receptors in hippocampal granule cells in order to clarify the basis of inhibitory synaptic plasticity induced by an experimental model of temporal-lobe epilepsy (a process known as kindling)(10). We find that the larger amplitude (66% increase) of elementary synaptic currents (quantal size) after kindling results directly from a 75% increase in the number of GABA(A) receptors at inhibitory synapses on somata and axon initial segments. Receptor density was up by 34-40% and the synaptic junctional area was expanded by 31%. Presynaptic boutons were enlarged, which may account for the 39% decrease in the average number of released transmitter packets (quantal content). Our findings establish the postsynaptic insertion of new GABA(A) receptors and the corresponding increase in postsynaptic responses augmenting the efficacy of mammalian inhibitory synapses.}, year = {1998}, eissn = {1476-4687}, pages = {172-177} } @article{MTMT:108772, title = {Segregation of different GABA~A receptors to synaptic and extrasynaptic membranes of cerebellar granule cells}, url = {https://m2.mtmt.hu/api/publication/108772}, author = {Nusser, Zoltán and Sieghart, W and Somogyi, Péter Pál}, doi = {10.1523/jneurosci.18-05-01693.1998}, journal-iso = {J NEUROSCI}, journal = {JOURNAL OF NEUROSCIENCE}, volume = {18}, unique-id = {108772}, issn = {0270-6474}, abstract = {Two types of GABA(A) receptor-mediated inhibition (phasic and tonic) have been described in cerebellar granule cells, although these cells receive GABAergic input only from a single cell type, the Golgi cell. In adult rats, granule cells express six GABA(A) receptor subunits abundantly (alpha 1, alpha 6, beta 2, beta 3, gamma 2, and delta), which are coassembled into at least four to six distinct GABA(A) receptor subtypes. We tested whether a differential distribution of GABA(A) receptors on the surface of granule cells could play a role in the different forms of inhibition, assuming that phasic inhibition originates from the activation of synaptic receptors, whereas tonic inhibition is provided mainly by extrasynaptic receptors. The alpha 1, alpha 6, beta 2/3, and gamma 2 subunits have been found by immunogold localizations to be concentrated in GABAergic Golgi synapses and also are present in the extrasynaptic membrane at a lower concentration. In contrast, immunoparticles for the delta subunit could not be detected in synaptic junctions, although they were abundantly present in the extrasynaptic dendritic and somatic membranes. Gold particles for the alpha 6, gamma 2, and beta 2/3, but not the alpha 1 and delta, subunits also were concentrated in some glutamatergic mossy fiber synapses, where their colocalization with AMPA-type glutamate receptors was demonstrated. The exclusive extrasynaptic presence of the delta subunit-containing receptors, together with their kinetic properties, suggests that tonic inhibition could be mediated mainly by extrasynaptic alpha(6) beta(2/3)delta receptors, whereas phasic inhibition is attributable to the activation of synaptic alpha(1) beta(2/3)gamma(2), alpha(6) beta(2/3)gamma(2), and alpha(1) alpha(6) beta(2/3)gamma(2) receptors.}, year = {1998}, eissn = {1529-2401}, pages = {1693-1703} } @article{MTMT:108773, title = {Differences in synaptic GABA~A receptor number underlie variation in GABA mini amplitude}, url = {https://m2.mtmt.hu/api/publication/108773}, author = {Nusser, Zoltán and Cull-Candy, S and Farrant, M}, doi = {10.1016/S0896-6273(00)80382-7}, journal-iso = {NEURON}, journal = {NEURON}, volume = {19}, unique-id = {108773}, issn = {0896-6273}, year = {1997}, eissn = {1097-4199}, pages = {697-709} } @article{MTMT:108778, title = {Theα6 subunit of the GABA~A receptor is concentrated in both inhibitory and excitatory synapses on cerebellar granule cells}, url = {https://m2.mtmt.hu/api/publication/108778}, author = {Nusser, Zoltán and Sieghart, W and Stephenson, FA and Somogyi, Péter Pál and Sieghart, W}, doi = {10.1523/jneurosci.16-01-00103.1996}, journal-iso = {J NEUROSCI}, journal = {JOURNAL OF NEUROSCIENCE}, volume = {16}, unique-id = {108778}, issn = {0270-6474}, year = {1996}, eissn = {1529-2401}, pages = {103-114} }