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Activity-mediated plasticity of GABA equilibrium potential in the CA1 region of the rat hippocampus

University of British Columbia

γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system (CNS). GABAA receptor mediated inhibitory postsynaptic currents (IPSCs) can affect both excitatory and inhibitory synapses, and thus, regulate CNS network activity. Amplitudes and the direction of IPSCs are subject to changes in the GABA equilibrium potential (EGABA). Changes in EGABA can affect various types of activity-dependent plasticity of the IPSC. Interestingly, EGABA is set at a more positive level in neonatal than that in adult central neurons, rendering GABA excitatory in neonates and inhibitory in adults. Therefore, mechanisms underlying activity-mediated as well as age-dependent plasticity of EGABA in rat hippocampus were examined in the current study. Since EGABA is mainly determined by the levels of intracellular Cl⁻ concentration ([Cl⁻]i) in central neurons, the activities of two cation-Cl⁻ cotransporters (K⁺⁻Cl⁻ cotransporter, KCC2 and Na⁺⁻K⁺⁻Cl⁻ cotransporter, NKCC1) contribute to changes in EGABA. Accordingly, factors which influence KCC2 or NKCC1 activity can induce shifts in EGABA. In this thesis, the involvement of GABAB receptors, metabotropic glutamate receptors (mGluRs), G-proteins and postsynaptic Ca²⁺ in the regulation of KCC2 or NKCC1 activity, and thus in EGABA in immature and juvenile hippocampal CA1 neurons were examined. Whole-cell patch recordings were made from hippocampal CA1 pyramidal neurons (from 9-12 or 3-5 day old rats), in a slice preparation. Glutamatergic excitatory postsynaptic currents were blocked with dl-2-Amino-5-phosphonovaleric acid (APV) and 6,7-dinitroquinoxaline-2,3-dione (DNQX). Western blot and immunohistochemistry methods were also used to monitor changes in receptor distribution and localization. The results indicate that shifts in EGABA are associated with several types of activity-mediated plasticity of IPSCs via changes in the activity of KCC2 or NKCC1 in hippocampal neurons. Interestingly, one type of specific, and behaviorally relavant, stimulation (theta burst stimulation, TBS) is able to induce a two-direction-shift in EGABA in juvenile and neonatal hippocampal neurons. GABAB receptors and G-porteins are involved in TBS-induced shifts in EGABA in juvenile hippocampal neurons while both postsynaptic Ca²⁺ and mGluRs appear to contribute to TBS-induced shifst in EGABA in both juvenile and neonatal neurons. However, the exact signal transduction pathways involving those above-mentioned factors awaits further investigation.

Text

2011-10-24

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/38164

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/