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The main inhibitory transmitter GABA in the adult brain has a fast hyperpolarizing effect by activating anion C1--permeant GABAA receptors. GABAA-receptor-mediated responses are often depolarizing during early neuronal development. This may be an important factor in the control of certain Ca(super2+)-dependent developmental phenomena. Ontogenetic changes in GABAA-mediated responses in pyramidal neurons of the rat hippocampus, from depolarizing to hyperpolarizing were found to be coupled to developmental induction of the expression of C1--extruding K+/C1- co-transporter, KCC2. It is concluded that KCC2 is the main C1- extruder in promoting fast hyperpolarizing postsynaptic brain inhibition.

ABSTRACT Adenosine inhibits excitatory neurons widely in the brain through adenosine A1 receptor, but activation of adenosine A2A receptor (A2AR) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A2AR expression level is low, and the receptor's effect on identified neuronal circuits is unknown. Using optogenetic afferent stimulation and whole-cell recording from identified postsynaptic neurons we show that A2AR facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons. In addition, A2AR enhances GABAergic inhibitory transmission between CA1 area interneurons leading to disinhibition of pyramidal cells. Adenosine A2AR has no direct modulatory effect on GABAergic synapses to pyramidal cells. As a result adenosine A2AR activation alters the synaptic excitation - inhibition balance in the CA1 area resulting in increased pyramidal cell discharge to glutamatergic Schaffer collateral stimulation. In line with this, we show that A2AR promotes synchronous pyramidal cell firing in hyperexcitable conditions where extracellular potassium is elevated or following high-frequency electrical stimulation. Our results revealed selective synapse- and cell type specific adenosine A2AR effects in hippocampal CA1 area. The uncovered mechanisms help our understanding of A2AR's facilitatory effect on cortical network activity. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Epileptic seizures are characterized by periods of hypersynchronous, hyperexcitability within brain networks. Most seizures involve two stages: an initial tonic phase, followed by a longer clonic phase that is characterized by rhythmic bouts of synchronized network activity called afterdischarges (ADs). Here we investigate the cellular and network mechanisms underlying hippocampal ADs in an effort to understand how they maintain seizure activity. Using in vitro hippocampal slice models from rats and mice, we performed electrophysiological recordings from CA3 pyramidal neurons to monitor network activity and changes in GABAergic signaling during epileptiform activity. First, we show that the highest synchrony occurs during clonic ADs, consistent with the idea that specific circuit dynamics underlie this phase of the epileptiform activity. We then show that ADs require intact GABAergic synaptic transmission, which becomes excitatory as a result of a transient collapse in the chloride (Cl-) reversal potential. The depolarizing effects of GABA are strongest at the soma of pyramidal neurons, which implicates somatic-targeting interneurons inADactivity. To test this, we used optogenetic techniques to selectively control the activity of somatic-targeting parvalbumin-expressing (PV+) interneurons. Channelrhodopsin-2-mediated activation of PV+ interneurons during the clonic phase generated excitatory GABAergic responses in pyramidal neurons, which were sufficient to elicit and entrain synchronousADactivity across the network. Finally, archaerhodopsin-mediated selective silencing ofPV+ interneurons reduced the occurrence of ADs during the clonic phase. Therefore, we propose that activity-dependent Cl- accumulation subverts the actions of PV+ interneurons to perpetuate rather than terminate pathological network hyperexcitability during the clonic phase of seizures. [ABSTRACT FROM AUTHOR]