Pharmacological enhancement of synaptic efficacy, spatial learning, and memory through carbonic anhydrase activation in rats.
CA1 pyramidal cells were recorded in rat hippocampal slices. In the presence of carbonic anhydrase activators, comicrostimulation of cholinergic inputs from stratum oriens and gamma-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.
Sun
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MK
Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland; and Laboratory of Adaptive Systems, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. mksun@brni-jhu-org
Alkon
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DL
D000086:Acetazolamide / Q000008:administration & dosage; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004558:Electric Stimulation; D004789:Enzyme Activation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects; D010649:Phenylalanine / Q000008:administration & dosage; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012153:Retention, Psychology / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D010649:Phenylalanine; D005680:gamma-Aminobutyric Acid; C029899:imidazole; D002256:Carbonic Anhydrases; D000109:Acetylcholine; D000086:Acetazolamide