Schizophrenia-related behavioral abnormalities in Shn-2 KO mice. (a, b) In the spatial working memory version of the eight-arm radial maze, Shn-2 KO mice performed significantly worse with respect to the number of different arm choices in the first eight entries (genotype effect: F1,24=62.104, P<0.0001) and made significantly more revisiting errors than controls (genotype effect: F1,24=45.597, P<0.0001; genotype × trial block interaction: F12,228=1.470, P=0.1345). (c) Mutant mice also showed poor working memory performance in the T-maze forced-alternation task (genotype effect: F1,21=20.497, P=0.0002; genotype × session interaction: F7,147=3.273, P=0.0029). (d) With increased delay, Shn-2 KO mice exhibited a lower correct percentage than controls (delay=3, 10, 30, and 60 s; P=0.0010, P=0.0047, P=0.0083, and P=0.0026, respectively). (e) Shn-2 KO and wild-type mice were comparable in the left–right discrimination task (genotype effect: F1,19=0.209, P=0.6529) and reversal learning (genotype effect: F1,19=5.917, P=0.0251). (f) The amplitude of the acoustic startle response was not significantly different between genotypes (Shn-2+/+, +Veh vs Shn-2−/−, Veh, F1,73=1.371, P=0.2454). (g) PPI of the acoustic startle response was impaired in Shn-2 KO mice (Shn-2+/+, Veh vs Shn-2−/−, Veh, 110 dB startle, P=0.0027; 120 dB startle, P=0.0003). Administration of haloperidol improved the PPI of Shn-2−/− mice (Shn-2−/−, Veh vs Shn-2−/−,1 mg/kg Hal, 110 dB, P=0.0145; 120 dB, P=0.0059; Shn-2−/−, Veh vs Shn-2−/−, 3 mg/kg Hal, 120 dB, P=0.0044). Post hoc Bonferroni's test after two-way repeated-measures ANOVA (level of significance was set at P<0.0167). (h) Shn-2 KO mice display a lower level of social approach in the sociability test. (i) Shn-2 KO mice did not show social novelty preference. (j) Shn-2 KO mice displayed decreased social interaction in a novel environment (total contact duration: F1,14=11.569, P=0.0043). (k) Administration of clozapine (1 mg/kg, i.p.) reversed hyperactivity in mutant mice (genotype effect: P=0.0012, drug effect: P=0.0003, genotype × drug interaction: P=0.0574, Shn-2−/−, Clz. vs Shn-2+/+, Veh., P=0.4221). (l) Administration of haloperidol (0.3 mg/kg, i.p.) also reduced hyperactivity in Shn-2 KO mice (genotype effect: P<0.0001, drug effect: P<0.0001, genotype × drug interaction: P=0.0275, Shn-2−/−, Hal. vs Shn-2+/+, Veh., P=0.8957). (m, n) Nest building was impaired in Shn-2 KO mice (P<0.0001). Veh, Vehicle; Clz, Clozapine; Hal, Haloperidol.