Potential Model of Carbonic Anhydrase Effects on Learning and Memory

Abstract

Cognition and memory deficits are common symptoms of many diseases affecting the central nervous system. Carbonic anhydrase (CA) is a zinc enzyme that catalyzes the reversible hydration of CO2 under physiological conditions and has a critical role in brain homeostasis and normal cerebral function. Decreased expression levels of CA enzymes are found in patients with Alzheimer’ Disease compared to a healthy adults and in the brains of older rats relative to younger rats. The CA1 pyramidal neurons which are involved in learning and memory receive three major inputs: cholinergic, glutamatergic, and GABAergic. In CA1 pyramidal cells, CA are located in different subcellular fractions such as mitochondrial, cytosolic, and membrane‐bound. Potentially, by activating CA enzymes in CA1 pyramidal neurons, learning and memory may occur by reversing the inhibitory action of GABA and the subsequent Cl− influx into cytoplasm by effluxing HCO3−. Therefore, our hypothesis is that efficient CA activators that cross the blood‐brain‐barrier will enhance learning and memory.Our objective is to design, synthesize, and profile a library of novel potent and lipophilic CA activators and test functional activity using simple learning and memory models in mice. Our strategy is to give CA activators alone and in combination with different amnesics, which interfere with the firing of CA1 pyramidal neurons. In the current studies, after profiling the activators for good physicochemical properties and in vitro profile, male, Swiss‐Webster mice were tested for their short term memory in a single day learning and memory operant conditioning task and a novel object recognition task. In the operant task, the mice were placed within experimental chambers and the acquisition and then the retention of a novel nose‐poke response in the presence of an audible tone was recorded. The mice were rewarded by 50 % Ensure solution for responses that occurred during the tone. A novel lipophilic CA activator, BD117, was tested alone and in the presence of the CA inhibitor acetazolamide. Acetazolamide produced decreased retention of the novel nose‐poke response suggesting CA inhibition can disrupt memory. However, BD117, the activator, produced no adverse or behavioral effects that interfered with learning or memory and produced a partial reversal of the inhibition produced by acetazolamide. In a standard novel object recognition task with retention test intervals of 30 min – 1 hour, CA activator, BD117 produced a small enhancement of novel object exploration without altering total exploration. BD117 produced no overt adverse or behavioral effects that interfered with learning or memory and produced a complete reversal of the inhibition produced by acetazolamide, scopolamine and partial retrieval from ketamine. Taken together, these data suggest CA activation is a promising strategy to explore for memory enhancement and the continued development of additional compounds in this series.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.