Mice lacking the epidermal growth factor receptor (EGFR) develop an early postnatal degeneration of the frontal cortex and olfactory bulbs and show increased cortical astrocyte apoptosis. The poor health and early lethality of EGFR/ mice prevented the analysis of mechanisms responsible for the neurodegeneration and function of the EGFR in the adult brain. Here, we show that postnatal EGFRdeficient neural stem cells are impaired in their selfrenewal potential and lack clonal expansion capacity in vitro. Mice lacking the EGFR in the brain (EGFRbrain) show low penetrance of cortical degeneration compared to EGFR/ mice despite genetic recombination of the conditional allele. Adult EGFR mice establish a proper bloodbrain barrier and perform reactive astrogliosis in response to mechanical and infectious brain injury, but are more sensitive to Kainic acidinduced epileptic seizures. EGFRdeficient cortical astrocytes, but not midbrain astrocytes, have reduced expression of glutamate transporters Glt1 and Glast, and show reduced glutamate uptake in vitro, illustrating an excitotoxic mechanism to explain the hypersensitivity to Kainic acid and regionspecific neurodegeneration observed in EGFRdeficient brains.