Glutamate transport is a critical process in the brain that maintains low 
extracellular levels of glutamate to allow for efficient neurotransmission and 
prevent excitotoxicity. Loss of glutamate transport function is implicated in 
epilepsy, traumatic brain injury, and amyotrophic lateral sclerosis. It remains 
unclear whether or not glutamate transport can be modulated in these disease 
conditions to improve outcome. Here, we show that sirtuin (SIRT)4, a 
mitochondrial sirtuin, is up-regulated in response to treatment with the potent 
excitotoxin kainic acid. Loss of SIRT4 leads to a more severe reaction to kainic 
acid and decreased glutamate transporter expression and function in the brain. 
Together, these results indicate a critical and novel stress response role for 
SIRT4 in promoting proper glutamate transport capacity and protecting against 
excitotoxicity.