Excitotoxicity: An Organized Crime at The Cellular Level

Abstract

Excitotoxicity is a form of neuronal death induced by increased Glutamate (Glu) signaling which has been implicated in the pathophysiology of a myriad of neuropsychiatric conditions, such as dementia, motor disorders and epilepsy, among many others. The molecular mechanisms underlying excitotoxicity involve alterations of Glu and ionic calcium metabolism, Glu receptor –particularly N-Methyl-D-Aspartate receptors (NMDARs)– and Glu transporter functioning, activation of downstream enzymes including phospholipases and proteases, and activation of pro-apoptotic mechanisms such as the conformation of mitochondrial permeability pores and release of pro-apoptotic factors. Different mechanisms appear to be more relevant in distinct acute or chronic contexts. Knowledge of these aspects has propelled use of NMDAR antagonists such as memantine in the therapeutic management of disorders where excitotoxicity is prominent. In this review, we explore the current views on the neurobiological and clinical aspects of excitotoxicity, presenting this process as a complex organized crime at the cellular level.