A role for N-methyl-D-aspartate receptors in norepinephrine-induced long-lasting potentiation in the dentate gyrus

Summary Mechanisms of action of norepinephrine (NE) on dentate gyrus granule cells were studied in rat hippocampal slices using extra- and intracellular recordings and measurements of stimulus and amino acid-induced changes in extracellular Ca²⁺ and K⁺ concentration. Bath application of NE (10–50 M) induced long-lasting potentiation of perforant path evoked potentials, and markedly enhanced high-frequency stimulus-induced Ca²⁺ influx and K⁺ efflux, actions blocked by -receptor antagonists and mimicked by agonists. Enhanced Ca²⁺ influx was primarily postsynaptic, since presynaptic [Ca²⁺]₀ in the stratum moleculare synaptic field was not altered by NE. Interestingly, the potentiation of both ionic fluxes and evoked population potentials were antagonized by the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (APV). Furthermore, NE selectively enhanced the [Ca²⁺]₀, [K⁺]₀ and extracellular slow negative field potentials elicited by iontophoretically applied NMDA, but not those induced by the excitatory amino acid quisqualate. These results suggest that granule cell influx of Ca²⁺ through NMDA ionophores is enhanced by NE via -receptor activation. In intracellular recordings, NE depolarized granule cells (4.8±1.1 mV), and increased input resistance (R_N) by 34±6.5%. These actions were also blocked by either the -antagonist propranolol or specific ₁-blocker metoprolol. Moreover, the depolarization and R_N increase persisted for long periods (93±12 min) after NE washout. In contrast, while NE, in the presence of APV, still depolarized granule cells and increased R_N, APV made these actions quickly reversible upon NE washout (16±9 min). This suggested that NE induction of long-term, but not short-term, plasticity in the dentate gyrus requires NMDA receptor activation. NE may be enhancing granule cell firing by some combination of blockade on the late Ca²⁺-activated K⁺ conductance and depolarization of granule cells, both actions that can bring granule cells into a voltage range where NMDA receptors are more easily activated. Furthermore, NE also elicited activity-independent long-lasting depolarization and R_N increases, which required functional NMDA receptors to persist.