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Exposure of cultured cortical neurons to elevated extracellular K+ concentrations (25 mM) induces membrane depolarization and an increase in action-potential firing. Long-term high K+ treatment was associated with an increased neuronal cell death. In surviving neurons, multiple changes occurred in the proportion of individual NMDA receptor subunit 1 (NR1) splice variant mRNA expression, whereas the overall expression of NR1, NR2A and NR2B transcripts remained unaffected. The high K+-induced changes in NR1 splice variant expression were virtually abolished upon a concurrent administration of tetrodotoxin (TTX; 3 μM). In voltage-clamp recordings performed on neurons resistant to high K+ treatment, inward currents induced by NMDA (1–1000 μM) were reduced. In K+-resistant cells, the activity of calpain but not of caspase-3 was diminished compared with controls kept in regular medium. NR function as well as calpain activity was not affected in cultures concomitantly treated with high K+ and either TTX or a NR antagonist (CGS19755 (selfotel) or memantine). In conclusion, the present data indicate adaptive changes in NR1 splice variant expression and a decrease in NR function upon a sustained increase in neurotransmission. Accordingly, alternative splicing could be an endogenous mechanism to counteract cellular damage due to overactivation of excitatory NRs and may be associated with an impairment of necrotic mechanisms. British Journal of Pharmacology (2006) 147, 622–633. doi:10.1038/sj.bjp.0706471