Genetic variants of the NMDA receptor influence cortical excitability and 1 plasticity in humans

33 NMDA receptors play crucial roles in glutamate-mediated synaptic transmission and plasticity, and 34 are involved in a variety of brain functions. Specific single nucleotide polymorphisms (SNPs) in the 35 genes encoding NMDA receptor subunits have been associated with some neuropsychiatric 36 disorders involving altered glutamate transmission, but how these polymorphisms impact on 37 synaptic function in humans is unknown. 38 Here, the role of NMDA receptors in the control of cortical excitability and plasticity was explored 39 by comparing the response to single, paired, and repetitive transcranial magnetic stimulations of the 40 motor cortex in 77 healthy subjects carrying specific allelic variants of the NR1 subunit gene 41 (GRIN1 rs4880213 and rs6293) or of the NR2B subunit gene (GRIN2B rs7301328, rs3764028, 42 rs1805247). 43 Our results showed that individuals homozygous for the T allele in the rs4880213 GRIN1 SNP had 44 reduced intracortical inhibition, as expected for enhanced glutamatergic excitation in these subjects. 45 Furthermore, individuals carrying the G allele in the rs1805247 GRIN2B SNP show greater 46 intracortical facilitation and greater long-term potentiation (LTP)-like cortical plasticity after 47 intermittent theta burst stimulation. 48 Our results provide novel insights into the function of NMDA receptors in the human brain, and 49 might contribute to the clarification of the synaptic bases of severe neuropsychiatric disorders 50 associated with defective glutamate transmission. 51 52