Three-dimensional chromosomal conformations regulate transcription by moving enhancers and reg-ulatory elements into spatial proximity with target genes. Here we describe activity-regulated long-range loopings bypassing up to 0.5 Mb of linear genome to modulate NMDA glutamate receptor GRIN2B expression in human and mouse prefrontal cortex. Distal intronic and 3 0 intergenic loop forma-tions competed with repressor elements to access promoter-proximal sequences, and facilitated ex-pression via a ''cargo'' of AP-1 and NRF-1 tran-scription factors and TALE-based transcriptional activators. Neuronal deletion or overexpression of Kmt2a/Mll1 H3K4-and Kmt1e/Setdb1 H3K9-methyl-transferase was associated with higher-order chro-matin changes at distal regulatory Grin2b sequences and impairments in working memory. Genetic poly-morphisms and isogenic deletions of loop-bound sequences conferred liability for cognitive perfor-mance and decreased GRIN2B expression. Dynamic regulation of chromosomal conformations emerges as a novel layer for transcriptional mechanisms im-pacting neuronal signaling and cognition. INTRODUCTION