Interleukin-2 modulates N-methyl-D-aspartate receptors of native mesolimbic neurons

Interleukin (IL)-2 is a brain-derived cytokine that influences mesocorticolimbic dopamine release, and is associated with pathological outcomes that are mediated, at least in part, by aberrations in mesolimbic neurotransmission. The mechanisms by which IL-2 modulates mesolimbic transmission, however, are not known. The NMDA receptor/channel (NMDAR) plays an essential role in neuronal excitability of mesolimbic neurons; we thus examined in neonatal rats the effects of IL-2 on NMDA-activated current (I_NMDA) in voltage-clamped neurons freshly isolated from the ventral tegmental area (VTA), the site of origin of the mesolimbic system. IL-2 (0.01-500 ng/ml) alone had no effect on membrane conductance. When co-applied with NMDA, IL-2 (50-500 ng/ml) significantly potentiated I_NMDA. In contrast, doses as low as 0.01 ng/ml markedly decreased the NMDA response. Dose-response analysis showed that IL-2 (>50 ng/ml) increased the maximal I_NMDA, without changing the EC₅₀, indicating that IL-2 potentiates I_NMDA by increasing the efficacy of the NMDAR. Moreover, current-voltage analysis revealed that IL-2 potentiation of I_NMDA was voltage-dependent, being greater at negative potentials. In contrast, IL-2 inhibition of I_NMDA was voltage-independent, and IL-2 did not alter the reversal potential. Additionally, IL-2 (1 ng/ml) shifted the NMDA concentration-response curve to the right, significantly increasing the EC₅₀ for NMDA without changing the maximal I_NMDA, suggesting that IL-2 inhibits the NMDAR by a competitive mechanism. IL-2 thus acts as a potent modulator of the NMDAR. IL-2-induced alterations of responses to NMDAR activation may contribute to synaptic plasticity in the mesolimbic system and to pathological outcomes associated with this system.