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The Journal of Neuroscience, July 11, 2007, 27(28):7438-7446; doi:10.1523/JNEUROSCI.2304-07.2007

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Cellular/Molecular
Endogenous Alkaline Transients Boost Postsynaptic NMDA Receptor Responses in Hippocampal CA1 Pyramidal Neurons

Sachin Makani and Mitchell Chesler

Departments of Neurosurgery and Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016

Correspondence should be addressed to Dr. Mitchell Chesler, Department of Physiology and Neuroscience, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Email: mitch.chesler{at}med.nyu.edu

In hippocampus, activation of the Schaffer collaterals generates an extracellular alkaline transient both in vitro and in vivo. This pH change may provide relief of the H⁺ block of NMDA receptors (NMDARs) and thereby increase excitability. To test this hypothesis, we augmented extracellular buffering in mouse hippocampal slices by adding 2 µM bovine type II carbonic anhydrase to the superfusate. With addition of enzyme, the alkaline transient elicited by a 10 pulse, 100 Hz stimulus train was reduced by 33%. At a holding potential (V_H) of –30 mV, the enzyme decreased the half-time of decay and charge transfer of EPSCs by 32 and 39%, respectively, but had no effect at a V_H of –80 mV. In current clamp, a 10 pulse, 100 Hz stimulus train gave rise to an NMDAR-dependent afterdepolarization (ADP). Exogenous enzyme curtailed the ADP half-width and voltage integral by 20 and 25%, respectively. Similar reduction of the ADP was noted with a brief 12 Hz stimulus train. The effect persisted in the presence of GABAergic antagonists or the L-type Ca²⁺ channel blocker methoxyverapamil hydrochloride but was absent in the presence of the carbonic anhydrase inhibitor benzolamide or when the exogenous enzyme was heat inactivated. The effects of the enzyme in voltage and current clamp were noted in 0 Mg²⁺ media but were abolished when (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate was included in the patch pipette. These results provide strong evidence that endogenous alkaline transients are sufficiently large in the vicinity of the synapse to augment NMDAR responses.

Key words: benzolamide; pH microelectrode; carbonic anhydrase; stratum radiatum; afterdepolarization; MK-801

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Received May 20, 2007; revised June 5, 2007; accepted June 5, 2007.

Correspondence should be addressed to Dr. Mitchell Chesler, Department of Physiology and Neuroscience, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Email: mitch.chesler{at}med.nyu.edu

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