Block of NMDA receptors by a newly synthesized analog of milnacipran in cultured mouse hippocampal neurons

Abstract

Immature hippocampal neurons with high input resistances (Rin) are vulnerable to hyperexcitable or epileptogenic conditions. This phenomenon has been suggested to explain the neuroprotective roles of hyperpolarization-activated cation channels (Ih channels) to regulate membrane Rin. In the present study, we tried to electrophysiologically clarify the relationship between membrane Rin and Ih channels and determine the neuroprotective roles of these channels in development. The CA1 neurons from rats (within 3 postnatal weeks) were classified into two groups based on the onset time (shorter or longer than 20 ms) to fire the first action potential (AP) in response to a current injection (100 pA, 800 ms). Neurons with a shorter onset time (Short-OsT), exhibited higher Rin, while neurons with longer onset times (Long-OsT) revealed lower Rin. Unexpectedly, Short-OsT neurons with higher Rin exhibited larger amplitudes of Ih compared with Long-OsT neurons. Furthermore, the application of temporal depolarization stimulus (TDS, −14 mV holding for 150 s) significantly enhanced suprathreshold excitabilities of repetitive APs in Long-OsT but not Short-OsT neurons, suggesting a protective role of Ih channels under high Rin conditions. In the presence of the specific hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker ZD7288, TDS also enhanced the excitability of Short-OsT neurons, suggesting that young CA1 neurons regulate Ih channel expression for neuroprotective modulation against epileptogenic conditions.