Unexpectedly, the three genes within or closest to the two largest deletions (c3orf58, NHE9, and PCDH10) were all independently identified by unbiased screens looking for genes regulated by neuronal activity or for targets of transcription factors induced by activity. Neuronal activity induces a set of transcription factors (including MEF2, NPAS4, CREB, EGR, SRF, and others) with time courses of minutes to hours, and these transcription factors induce or repress specific target genes that mediate synaptic development and plasticity (34). This activity-based gene expression results in protein changes that selectively enhance or repress synapses, likely forming a part of learning paradigms (35). In microarray screens using cultured rat hippocampal neurons (performed blind to the genetic study), 1005 complementary DNAs (cDNAs) (of 22,407 nonredundant genes tested, i.e., ≈5% of the transcriptome) were identified as altered in expression after neuronal membrane depolarization by elevated KCl (21). Among these “neural activity–regulated” genes, c3orf58 (deleted in patient AU-3101) was robustly increased within 6 hours of membrane depolarization (Fig. 3A). c3orf58 contained several evolutionarily conserved binding sites for MEF2, CREB, and SRF (Fig. 3B), and depolarization-dependent
