Neurexins are synaptic adhesion proteins encoded by 3 genes (NRXN1, NRXN2, and NRXN3) each transcribed from 2 promoters to yield longer (a) and shorter (P) forms. The primary gene transcripts undergo extensive alternative splicing leading to products that may differ in synaptic coupling properties. Here we show that depolarization of neurons modulates splicing of NRXN2 alpha, particularly at splice sites 1 and 3. Furthermore, we demonstrate that exclusion of exon 11 at splice site 3 is calcium-dependent. These data indicate neuronal activity-dependent splicing of NRXN2 alpha. This dynamic process may be important for maintenance of mature neuronal circuits. (c) 2006 Elsevier Inc. All rights reserved.