Recovery from neuronal activation requires rapid clearance of potassium ions (K ؉ ) and restoration of osmotic equilibrium. The predominant water channel protein in brain, aquaporin-4 (AQP4), is concentrated in the astrocyte end-feet membranes adjacent to blood vessels in neocortex and cerebellum by association with ␣-syntrophin protein. Although AQP4 has been implicated in the pathogenesis of brain edema, its functions in normal brain physiology are uncertain. In this study, we used immunogold electron microscopy to compare hippocampus of WT and ␣-syntrophin-null mice (␣-Syn ؊/؊ ). We found that <10% of AQP4 immunogold labeling is retained in the perivascular astrocyte end-feet membranes of the ␣-Syn ؊/؊ mice, whereas labeling of the inwardly rectifying K ؉ channel, Kir4.1, is largely unchanged. Activity-dependent changes in K ؉ clearance were studied in hippocampal slices to test whether AQP4 and K ؉ channels work in concert to achieve isosmotic clearance of K ؉ after neuronal activation. Microelectrode recordings of extracellular K ؉ ([K ؉ ]o) from the target zones of Schaffer collaterals and perforant path were obtained after 5-, 10-, and 20-Hz orthodromic stimulations. K ؉ clearance was prolonged up to 2-fold in ␣-Syn ؊/؊ mice compared with WT mice. Furthermore, the intensity of hyperthermia-induced epileptic seizures was increased in approximately half of the ␣-Syn ؊/؊ mice. These studies lead us to propose that water flux through perivascular AQP4 is needed to sustain efficient removal of K ؉ after neuronal activation.

The postsynaptic actions of acetylcholine, adenosine, yaminobutyric acid, histamine, norepinephrine, and serotonin were analyzed in human cortical pyramidal cells maintained in vitro. The actions of these six putative neurotransmitters converged onto three distinct potassium currents.Application of acetylcholine, histamine, norepinephrine, or serotonin all increased spiking by reducing spike-frequency adaptation, in part by reducing the current that underlies the slow afterhyperpolarization. In addition, application of muscarinic receptor agonists to all neurons or of serotonin to middle-layer cells substantially reduced or blocked the Mcurrent (a K+ current that is voltage and time dependent).Inhibition of neuronal firing was elicited by adenosine, baclofen (a yaminobutyric acid type B receptor agonist), or serotonin and appeared to be due to an increase in the same potassium current by all three agents. These data reveal that individual neuronal currents in the human cerebral cortex are under the control of several putative neurotransmitters and that each neurotransmitter may exhibit more than one postsynaptic action. The specific anatomical connections of these various neurotransmitter systems, as well as their heterogeneous distribution of postsynaptic receptors and responses, allows each to make a specific contribution to the modulation of cortical activity.