title: Effects of memantine on the excitation-inhibition balance in prefrontal cortex.
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 thought to be mediated by parvalbumin (PV)-positive interneurons. Accordingly, memantine caused a greater decrease of the amplitude of NMDAR-mediated synaptic responses in PV-positive interneurons than in pyramidal neurons. Finally, memantine reduced firing activity in PV-positive interneurons while increasing firing in pyramidal neurons. This study elucidates a novel mechanism of action of memantine associated with shifting of the E/I balance away from inhibition in neocortical circuitry, and provides important insights for AD drug development.
authors.affiliation: Department of Neuroscience, and Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, United States. Electronic address: nvp1@pitt.edu.
authors.forename: Nadezhda V
authors.initials: NV
authors.lastname: Povysheva
authors.affiliation: Department of Neuroscience, and Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, United States; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260, United States. Electronic address: jjohnson@pitt.edu.
authors.forename: Jon W
authors.initials: JW
authors.lastname: Johnson
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D010320:Parvalbumins; D011724:Pyridazines; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C056639:2-amino-5-phosphopentanoic acid; C049853:gabazine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D014633:Valine; D008559:Memantine
keywords: Alzheimer's disease; Channel block; Excitation/inhibition balance; Inhibition; Memantine; NMDA receptors; Prefrontal cortex; Whole-cell recording