RT Journal Article
SR Electronic
T1 Altered chloride homeostasis decreases the action potential threshold and increase hyperexcitability in hippocampal neurons
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0172-17.2017
DO 10.1523/ENEURO.0172-17.2017
A1 Andreas T. Sørensen
A1 Marco Ledri
A1 Miriam Melis
A1 Litsa Nikitidou Ledri
A1 My Andersson
A1 Merab Kokaia
YR 2017
UL http://www.eneuro.org/content/early/2017/12/07/ENEURO.0172-17.2017.abstract
AB Chloride ions play an important role in controlling excitability of principal neurons in the central nervous system. When neurotransmitter GABA is released from inhibitory interneurons, activated GABAA receptors on principal neurons become permeable to chloride. Typically, chloride flows through activated GABAA receptors into the neurons causing hyperpolarization or shunting inhibition, and in turn inhibits action potential (AP) generation. However, in situations when intracellular chloride concentration is increased, chloride ions can flow in opposite direction, depolarize neurons and promote AP generation. It is generally recognized that altered chloride homeostasis per se has no effect on the AP threshold. Here we demonstrate that chloride overload of mouse principal CA3 pyramidal neurons not only makes these cells more excitable through GABAA receptor activation, but also lowers the AP threshold, further aggravating excitability. This phenomenon has not been described in principal neurons, and adds to our understanding of mechanisms regulating neuronal and network excitability, particularly in developing brain and during pathological situations with altered chloride homeostasis. This finding further broadens the spectrum of neuronal plasticity regulated by ionic compositions across the cellular membrane.Significance Statement Here we report that chloride loading, either directly via the recording electrode or indirectly by long-lasting optogenetic activation of Halorhodopsin, in the hippocampal CA3 region causes a substantial reduction in the action potential threshold and aberrant GABAA receptor mediated excitatory activity in individual neurons and networks. Since intracellular chloride accumulation occurs in the developing brain and during pathologic conditions, resetting the action potential threshold by chloride might represent a novel mechanism for regulating excitability.