Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Here, we show that polyglutamine-expanded AR accumulates in the nucleus of motor neurons and induces aberrant up-regulation of glutamatergic synaptic genes, mediated by a master transcriptional repressor, Rest, during early postnatal development in a mouse model of SBMA. Further analysis indicates that the up-regulation of Rest-target synaptic genes is caused by an increased expression of Rest4, a neuron-specific isoform of Rest that derepresses the promoter activity of Rest-binding lesions. In addition, calcium imaging shows that induced pluripotent stem cell-derived motor neurons expressing polyglutamine-expanded AR are hyperexcitable compared to those expressing wild-type AR. Reducing neonatal AR or switching Rest4 to Rest using antisense oligonucleotides attenuates the up-regulation of the synaptic genes and ameliorates the disease phenotype and histopathology in SBMA mice. The late-onset neurodegeneration in SBMA is attributable to the synaptic defects and resulting hyperexcitability of motor neurons at early postnatal stages, which would be therapeutically targeted.