Effects of memantine on the excitation-inhibition balance in prefrontal cortex

Neurobiology of Disease
Nadezhda V Povysheva, Jon W Johnson

Abstract

Memantine is one of the few drugs currently approved for treatment of Alzheimer's disease (AD). The clinical effects of memantine are thought to be associated with inhibition of NMDA receptors (NMDARs). Surprisingly, other open-channel NMDAR blockers have unacceptable side effects that prevent their consideration for AD treatment. One of the mechanisms proposed to explain the therapeutic benefits of memantine involves preferential decrease of excitatory drive to inhibitory neurons in the cortical circuitry and consequent changes in balance between excitation and inhibition (E/I). In this study we addressed effects of memantine on E/I balance in the prefrontal cortex (PFC). We found that a moderate concentration of memantine shifted E/I balance away from inhibition in the PFC circuitry. Indeed, memantine decreased the frequency and amplitude of spontaneous inhibitory postsynaptic currents in pyramidal neurons while leaving spontaneous excitatory postsynaptic currents unaffected. These circuitry effects of memantine were occluded by the competitive NMDAR inhibitor AP-5, and thus are associated with NMDAR inhibition. We also found that memantine decreased feed-forward disynaptic inhibitory input to pyramidal neurons, which is thou...Continue Reading

References

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Citations

Apr 21, 2017·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Gregory A LightNeal R Swerdlow
Jan 11, 2018·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Mary M Torregrossa
Oct 21, 2017·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Emily L NewmanKlaus A Miczek
May 10, 2017·Journal of Alzheimer's Disease : JAD·Izumi MaezawaLee-Way Jin
Mar 14, 2018·Proceedings of the National Academy of Sciences of the United States of America·Allie J Widman, Lori L McMahon

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