The dyslexia-associated gene DCDC2 is required for spike-timing precision in mouse neocortex.

BACKGROUND:Variants in dyslexia-associated genes, including DCDC2, have been linked to altered neocortical activation, suggesting that dyslexia associated genes might play as yet unspecified roles in neuronal physiology. METHODS:Whole-cell patch clamp recordings were used to compare the electrophysiological properties of regular spiking pyramidal neurons of neocortex in Dcdc2 knockout (KO) and wild-type mice. Ribonucleic acid sequencing and reverse transcriptase polymerase chain reaction were performed to identify and characterize changes in gene expression in Dcdc2 KOs. RESULTS:Neurons in KOs showed increased excitability and decreased temporal precision in action potential firing. The RNA sequencing screen revealed that the N-methyl-D-aspartate receptor (NMDAR) subunit Grin2B was elevated in Dcdc2 KOs, and an electrophysiological assessment confirmed a functional increase in spontaneous NMDAR-mediated activity. Remarkably, the decreased action potential temporal precision could be restored in mutants by treatment with either the NMDAR antagonist (2R)-amino-5-phosphonovaleric acid or the NMDAR 2B subunit-specific antagonist Ro 25-6981. CONCLUSIONS:These results link the function of the dyslexia-associated gene Dcdc2 to spike timing through activity of NMDAR.

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