Mironov, Sergej L.

[["dc.bibliographiccitation.artnumber","e0202802"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","PLOS ONE"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Balakrishnan, Saju"],["dc.contributor.author","Mironov, Sergej L."],["dc.date.accessioned","2019-07-09T11:46:07Z"],["dc.date.available","2019-07-09T11:46:07Z"],["dc.date.issued","2018"],["dc.description.abstract","Excess glutamate during intense neuronal activity is not instantly cleared and may accumulate in the extracellular space. This has various long-term consequences such as ectopic signaling, modulation of synaptic efficacy and excitotoxicity; the latter implicated in various neurodevelopmental and neurodegenerative diseases. In this study, the quantitative imaging of glutamate homeostasis of hippocampal slices from methyl-CpG binding protein 2 knock-out (Mecp2-/y) mice, a model of Rett syndrome (RTT), revealed unusual repetitive glutamate transients. They appeared in phase with bursts of action potentials in the CA1 neurons. Both glutamate transients and bursting activity were suppressed by the blockade of sodium, AMPA and voltage-gated calcium channels (T- and R-type), and enhanced after the inhibition of HCN channels. HCN and calcium channels in RTT and wild-type (WT) CA1 neurons displayed different voltage-dependencies and kinetics. Both channels modulated postsynaptic integration and modified the pattern of glutamate spikes in the RTT hippocampus. Spontaneous glutamate transients were much less abundant in the WT preparations, and, when observed, had smaller amplitude and frequency. The basal ambient glutamate levels in RTT were higher and transient glutamate increases (spontaneous and evoked by stimulation of Schaffer collaterals) decayed slower. Both features indicate less efficient glutamate uptake in RTT. To explain the generation of repetitive glutamate spikes, we designed a novel model of glutamate-induced glutamate release. The simulations correctly predicted the patterns of spontaneous glutamate spikes observed under different experimental conditions. We propose that pervasive spontaneous glutamate release is a hallmark of Mecp2-/y hippocampus, stemming from and modulating the hyperexcitability of neurons."],["dc.identifier.doi","10.1371/journal.pone.0202802"],["dc.identifier.pmid","30256804"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15395"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59378"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.intern","In goescholar not merged with http://resolver.sub.uni-goettingen.de/purl?gs-1/15697 but duplicate"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Regenerative glutamate release in the hippocampus of Rett syndrome model mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","363"],["dc.bibliographiccitation.journal","Frontiers in Cellular Neuroscience"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Balakrishnan, Saju"],["dc.contributor.author","Mironov, Sergej L."],["dc.date.accessioned","2019-07-09T11:46:08Z"],["dc.date.available","2019-07-09T11:46:08Z"],["dc.date.issued","2018"],["dc.description.abstract","Rett syndrome (RTT) is a neurological disorder caused by the mutation of the X-linked MECP2 gene. The neurophysiological hallmark of the RTT phenotype is the hyperexcitability of neurons made responsible for frequent epileptic attacks in the patients. Increased excitability in RTT might stem from impaired glutamate handling in RTT and its long-term consequences that has not been examined quantitatively. We recently reported (Balakrishnan and Mironov, 2018a,b) that the RTT hippocampus consistently demonstrates repetitive glutamate transients that parallel the burst firing in the CA1 neurons. We aimed to examine how brief stimulation of specific types of ionotropic and metabotropic glutamate receptors (GluR) can modulate the neuronal phenotype. We imaged glutamate with a fluorescence sensor (iGluSnFr) expressed in CA1 neurons in hippocampal organotypic slices from wild-type (WT) and Mecp2-/y mice (RTT). The neuronal and synaptic activities were assessed by patch-clamp and calcium imaging. In both WT and RTT slices, activation of AMPA, kainate, and NMDA receptors for 30 s first enhanced neuronal activity that induced a global release of glutamate. After transient augmentation of excitability and ambient glutamate, they subsided. After wash out of the agonists for 10 min, WT slices recovered and demonstrated repetitive glutamate transients, whose pattern resembled those observed in naïve RTT slices. Hyperpolarization-activated (HCN) decreased and voltage-sensitive calcium channel (VSCC) currents increased. The effects were long-lasting and bigger in WT. We examined the role of mGluR1/5 in more detail. The effects of the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) were the same as AMPA and NMDA and occluded by mGluR1/5 antagonists. Further modifications were examined using a non-stationary noise analysis of postsynaptic currents. The mean single channel current and their number at postsynapse increased after DHPG. We identified new channels as calcium-permeable AMPARs (CP-AMPAR). We then examined back-propagating potentials (bAPs) as a measure of postsynaptic integration. After bAPs, spontaneous afterdischarges were observed that lasted for ∼2 min and were potentiated by DHPG. The effects were occluded by intracellular CP-AMPAR blocker and did not change after NMDAR blockade. We propose that brief elevations in ambient glutamate (through brief excitation with GluR agonists) specifically activate mGluR1/5. This modifies CP-AMPAR, HCN, and calcium conductances and makes neurons hyperexcitable. Induced changes can be further supported by repetitive glutamate transients established and serve to persistently maintain the aberrant neuronal RTT phenotype in the hippocampus."],["dc.identifier.doi","10.3389/fncel.2018.00363"],["dc.identifier.pmid","30386209"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15402"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59384"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","CA1 Neurons Acquire Rett Syndrome Phenotype After Brief Activation of Glutamatergic Receptors: Specific Role of mGluR1/5"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e0195094"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","PlOS ONE"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Balakrishnan, Saju"],["dc.contributor.author","Mironov, Sergej L."],["dc.date.accessioned","2019-07-09T11:45:26Z"],["dc.date.available","2019-07-09T11:45:26Z"],["dc.date.issued","2018"],["dc.description.abstract","Hyperventilation is a known feature of Rett syndrome (RTT). However, how hyperventilation is related to other RTT symptoms such as hyperexcitability is unknown. Intense breathing during hyperventilation induces hypocapnia and culminates in respiratory alkalosis. Alkalinization of extracellular milieu can trigger epilepsy in patients who already have neuronal hyperexcitability. By combining patch-clamp electrophysiology and quantitative glutamate imaging, we compared excitability of CA1 neurons of WT and Mecp2 (-/y) mice, and analyzed the biophysical properties of subthreshold membrane channels. The results show that Mecp2 (-/y) CA1 neurons are hyperexcitable in normal pH (7.4) and are increasingly vulnerable to alkaline extracellular pH (8.4), during which their excitability increased further. Under normal pH conditions, an abnormal negative shift in the voltage-dependencies of HCN (hyperpolarization-activated cyclic nucleotide-gated) and calcium channels in the CA1 neurons of Mecp2 (-/y) mice was observed. Alkaline pH also enhanced excitability in wild-type (WT) CA1 neurons through modulation of the voltage dependencies of HCN- and calcium channels. Additionally alkaline pH augmented spontaneous glutamate release and burst firing in WT CA1 neurons. Conversely, acidic pH (6.4) and 8 mM Mg2+ exerted the opposite effect, and diminished hyperexcitability in Mecp2 (-/y) CA1 neurons. We propose that the observed effects of pH and Mg2+ are mediated by changes in the neuronal membrane surface potential, which consecutively modulates the gating of HCN and calcium channels. The results provide insight to pivotal cellular mechanisms that can regulate neuronal excitability and help to devise treatment strategies for hyperexcitability induced symptoms of Rett syndrome."],["dc.identifier.doi","10.1371/journal.pone.0195094"],["dc.identifier.pmid","29621262"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15207"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59230"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Rescue of hyperexcitability in hippocampal CA1 neurons from Mecp2 (-/y) mouse through surface potential neutralization"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]