Caspase-mediated suppression of glutamate (AMPA) receptor channel activityin hippocampal neurons in response to DNA damage promotes apoptosis and prevents necrosis: Implications for neurological side effects of cancer therapy and neurodegenerative disorders

DNA damage in neurons is implicated in the pathogenesis of several neurodeg enerative disordersand may also contribute to the often severe neurological complications in cancer patients treated with chemotherapeutic agents. DNA damage can trigger apoptosis, a form of controlled cell death that involve s activation of cysteine proteases called caspases. The excitatory neurotra nsmitter glutamate plays central roles in the activation of neurons and in processes such as learning and memory, but overactivation of ionotropic glu tamate receptors can induce either apoptosis or necrosis. Glutamate recepto rs of the AMPA (Phi -amino-3-hydroxy-5-methylisoxazole-4-propionate) type m ediate such physiological and pathological processes in most neurons. We no w report that DNA damage can alter glutamate receptor channel activity by a mechanism involving activation of caspases. Whole-cell patch clamp analyse s revealed a marked decrease in AMPA-induced currents after exposure of neu rons to camptothecin, a topoisomerase inhibitor that induces DNA damage; N- methyr-D-aspartate (NMDA)-induced currents were unaffected by camptothecin. The decrease in AMPA-induced current was accompanied by a decreased calciu m response to AMPA. pharmacological inhibition of caspases abolished the ef fects of camptothecin on AMPA-induced current and calcium responses, and pr omoted excitotoxic necrosis. Combined treatment with glutamate receptor ant agonists and a caspase inhibitor prevented camptothecin-induced neuronal de ath. Caspase-mediated suppression of AMPA currents may allow neurons with d amaged DNA to withdraw their participation in excitatory circuits and under go apoptosis, thereby avoiding widespread necrosis. These findings have imp ortant implications for treatment of patients with cancer and neurodegenera tive disorders. (C) 2001 Academic press.