Vol. 297, Issue 3, 961-967, June 2001

Pharmacological Enhancement of Synaptic Efficacy, Spatial Learning, and Memory through Carbonic Anhydrase Activation in Rats

Miao-Kun Sun and Daniel L. Alkon

Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland; and Laboratory of Adaptive Systems, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

CA1 pyramidal cells were recorded in rat hippocampal slices. In the presence of carbonic anhydrase activators, comicrostimulation of cholinergic inputs from stratum oriens and -aminobutyric acid (GABA)ergic inputs from stratum pyramidale at low intensities switched the hyperpolarizing GABA-mediated inhibitory postsynaptic potentials to depolarizing responses. In the absence of the activators, however, the same stimuli were insufficient to trigger the synaptic switch. This synaptic switch changed the function of the GABAergic synapses from excitation filter to amplifier and was prevented by carbonic anhydrase inhibitors, indicating a dependence on HCO. Intralateral ventricular administration of these same carbonic anhydrase activators caused the rats to exhibit superior learning of the Morris water maze task, suggesting that the GABAergic synaptic switch is critical for gating the synaptic plasticity that underlies spatial memory formation. Increased carbonic anhydrase activity might, therefore, also enhance perception, processing, and storing of temporally associated relevant signals and represents an important therapeutic target in learning and memory pharmacology.