Fig. 5.
H2R knockdown causes neuronal hypoactivity via enhancement of HCN Ih currents, and blocking HCN rescues schizophrenia-like phenotypes. (A) Representative hyperpolarization-activated Ih currents mediated by HCN channels. Ih (HCN current) was calculated by measuring the amplitude of current generated at voltages from −60 mV to −130 mV for 200 ms, with 10 mV increments. (B1) HCN currents evoked by −130 mV and (B2) by hyperpolarizing 20 mV steps from −130 mV to −60 mV. n = 29 cells from five CaMKIIα-Cre+AAV-FLEX-scramble shRNA-GFP mice (AAV-CON), n = 32 cells from six CaMKIIα-Cre+AAV-FLEX-shHrh2-GFP mice (AAV-shHrh2). (C) AP frequency after incubation with 50 μM ZD7288. n = 7 cells from four CaMKIIα-Cre+AAV-CON mice, n = 10 cells from five CaMKIIα-Cre+AAV-shHrh2 mice. (D) Abridged general view of the position of the cannula. (E–G) Sensorimotor gating ability, locomotion, and social behavior of CaMKIIα-Cre mice infected with AAV-CON or AAV-shHrh2 in the mPFC and then treated with saline or the HCN inhibitor ZD7288. n = 9 mice for each group. (E) Percentage of PPI of the auditory startle reflex under 74, 78, and 82 dB prepulse intensities. (F) Distance traveled in the open field every 5 min (Left) and the total distance traveled in the open field (Right) after administration of MK-801. (G) Social behavior evaluated by a three-chamber test. Time in close interaction and preference index for S1 and E in phase 2 and for S2 and S1 in phase 3. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. See also Dataset S1 for further statistical information.