Mosaic synapses in epilepsy

Mismatch of synaptic cadherins perturbs hippocampal circuitry The inherited X-linked early-onset childhood epilepsy, called EFMR (epilepsy and mental retardation limited to females), has baffled clinicians and geneticists for more than 50 years. In contrast to other X-linked disorders in which the hemizygous (hemi) male, but not the heterozygous (het) female is affected, it is only the het females that exhibit seizures and intellectual disability ( 1 , 2 ). Clues to the origin of this enigmatic disorder came when deleterious mutations in the X chromosome gene protocadherin-19 ( PCDH19 ), which encodes a cell adhesion molecule, were identified ( 3 ). On page 255 of this issue, Hoshina et al. ( 4 ) provide answers to two pieces of the EFMR puzzle: They reveal that hippocampal synaptic transmission is compromised in Pcdh19 het female mice but not in hemi males, and they provide a molecular explanation for how the retention of one wild-type (WT) allele, but not the loss of both alleles, disrupts neuronal connectivity.