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In part, this may be due to variable cortical neuron orientation relative to the electric field. We tested, in vivo and in vitro, whether DCS\u2010LTD occurs throughout the cortical thickness, and if not, then whether drug\u2013DCS pairing can enhance the uniformity of the cortical response and the cDCS antiepileptic effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>cDCS\u2010mediated changes in cortical excitability were measured in vitro in mouse motor cortex (M1) and in human postoperative neocortex, in vivo in mouse somatosensory cortex (S1), and in a mouse kainic acid (KA)\u2010seizure model. Contributions of N\u2010methyl\u2010D\u2010aspartate\u2013type glutamate receptors (NMDARs) to cDCS\u2010mediated plasticity were tested with application of NMDAR blockers (memantine\/D\u2010AP5).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>cDCS reliably induced DCS\u2010LTD in superficial cortical layers, and a long\u2010term potentiation (LTP)\u2010like enhancement (DCS\u2010LTP) was recorded in deep cortical layers. Immunostaining confirmed layer\u2010specific increase of phospho\u2010S6 ribosomal protein in mouse M1. Similar nonuniform cDCS aftereffects on cortical excitability were also found in human neocortex in vitro and in S1 of alert mice in vivo. Application of memantine\/D\u2010AP5 either produced a more uniform DCS\u2010LTD throughout the cortical thickness or at least abolished DCS\u2010LTP. Moreover, a combination of memantine and cDCS suppressed KA\u2010induced seizures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>cDCS aftereffects are not uniform throughout cortical layers, which may explain the incomplete cDCS clinical efficacy. NMDAR antagonists may augment cDCS efficacy in epilepsy and other disorders where regional depression of cortical excitability is desirable. 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