GABAergic Signaling and Neuronal Chloride Regulation in the Control of Network Events in the Immature Hippocampus

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http://urn.fi/URN:ISBN:978-951-51-5209-1
Title: GABAergic Signaling and Neuronal Chloride Regulation in the Control of Network Events in the Immature Hippocampus
Author: Spoljaric, Inkeri
Contributor: University of Helsinki, Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences and Neuroscience Center (HiLIFE)
Doctoral Programme Brain and Mind
Thesis level: Doctoral dissertation (article-based)
Belongs to series: DSHealth Doctoral Thesis series - URN:ISSN:2342-317X
Abstract: Spontaneously arising network events are a characteristic feature of all developing neural networks. This activity is crucial for normal neuronal development and the establishment of appropriate synaptic connectivity. In the developing hippocampus, depolarizing GABAergic drive is essential in generation of early network events, known as giant depolarizing potentials (GDPs). Blockade of GABAergic signaling leads to hypersynchronization of the network and emergence of ictal-like events, pointing to dual, both excitatory and inhibitory roles for GABA, in regulation of these events. In Studies I-III of this thesis, we examined the role of GABAA receptor (GABAAR) -mediated neurotransmission with some parallel work on glycinergic signaling as well as neuronal Cl- regulation in modulation of GDPs in the developing rodent hippocampus. In Study I, we demonstrate that low levels of GABA and glycine suppress GDPs by activating extrasynaptic receptors. This implies that regardless of the depolarizing drive for Cl- currents at this developmental stage, a low conductance via Cl- -permeable GABAARs and glycine receptors (GlyRs) can cause efficient shunting and inhibition of the network events. In Study II, we discovered that sustained activation of a subset of hippocampal interneurons, caused by the neuropeptide arginine vasopressin (AVP), silences the network events in the perinatal hippocampus, regardless of the maturational level of the GABAergic system as compared across species. This is attributed to decreased synchronous interneuronal input that is essential for the GDP generation. In Study III, we demonstrate that transport-functional K-Cl cotransporter 2 (KCC2) is present in the CA3 pyramidal neurons already in the perinatal stages in mice and rats. Cl- extrusion by KCC2 counteracts the dominant Na-K-2Cl cotransporter 1 (NKCC1) -mediated Cl- uptake and restrains the depolarizing GABAergic drive onto the CA3 pyramidal cells. Thereby, function of KCC2 limits pyramidal neuron spiking and synchronization during GDPs and participates in the modulation of GDPs from their developmental onset. This work describes novel physiological GABAergic mechanisms that control GDPs in the perinatal rodents and establishes a role for KCC2 in regulation of pyramidal neuron excitability and synchronization during GDPs starting from their developmental onset.Lukemattomat tutkimukset ovat osoittaneet, että spontaanisti syntyvä synkroninen aktiivisuus on kaikille kehittyville hermoverkoille ominainen piirre. Aktiivisuus ja sen laukaisemat signalointikaskadit tukevat hermosolujen normaalia kehitystä ja ohjaavat oikeiden hermoyhteyksien muodostumista. Kehittyvän hippokampuksen alueella solujen korkeasta kloriditasosta johtuva depolaarinen GABA ajaa GDP:inä (giant depolarizing potentials) tunnettuja synkronisia verkkotason aktiivisuusryöppyjä. GABAergisen signaloinnin hiljentäminen johtaa kuitenkin epileptisen aktiivisuuden muodostumiseen hermoverkossa, viitaten siihen, että GABAn rooli kehittyvässä hippokampuksessa on kaksisuuntainen: sekä hillitsevä, että kiihdyttävä. Tämän väitöskirjan osatöissä I-III tutkin sähköfysiologisin menetelmin GABA A-reseptorivälitteisen viestinnän ja solujen kloridisäätelyn roolia GDP:iden säätelyssä perinataaleissa hiirissä ja rotissa. Työssäni esittelen uusia fysiologisia mekanismeja GABA-välitteisessä GDP:iden säätelyssä ja osoitan ensimmäistä kertaa kloridikuljettaja KCC2:n keskeisen roolin pyramidisolujen ärtyvyyden ja verkkotason aktiivisuuden säätelyssä kehittyvässä hippokampuksessa. .
URI: URN:ISBN:978-951-51-5209-1
http://hdl.handle.net/10138/301114
Date: 2019-05-17
Subject: Physiology and Neuroscience
Rights: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.


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