Genes with essential roles in synaptic plasticity have been implicated as an important cause of autism (e.g. NRXN1, NLGN3/4X, SHANK2/3) [29], [30], and since many synaptic plasticity genes are regulated by neuronal depolarization [11], [31], we tested the degree to which our autism candidate genes showed expression that could be modulated by neuronal activity. We depolarized mouse cortical neuron cultures and assayed changes in gene expression levels. We found that four out of four of the mouse homologs of our candidate genes are upregulated in response to neuronal activity (UBE3B, CLTCL1/Cltc, NCKAP5L, and ZNF18/Zkscan6) (Figure 3). This is particularly interesting because in general only about 1000 transcripts, or about 3% of the transcriptome, manifest such depolarization-regulated gene transcription [32]. The upregulation of Ube3b in response to depolarization resembles the activity-dependent transcription of its close paralog Ube3a, which has well-documented roles in synaptic plasticity [26], [27]. The regulation of expression of several potential recessive autism genes by neuronal depolarization suggests that the candidate genes are likely to be involved in neuronal function and/or development, and mutations in these genes might lead to nervous system dysfunction in the context of autism spectrum disorders (ASDs).
