Histone deacetylase inhibitors mitigate antipsychotic risperidone-induced motor side effects in aged mice and in a mouse model of Alzheimer's disease

Abstract

Antipsychotic drugs are still widely prescribed to control various severe neuropsychiatric symptoms in the elderly and dementia patients although they are off-label use in the United States. However, clinical practice shows greater side effects and lower efficacy of antipsychotics for this vulnerable population and the mechanisms surrounding this aged-related sensitivity are not well understood. Our previous studies have shown that aging-induced epigenetic alterations may be involved in the increasing severity of typical antipsychotic haloperidol induced side effects in aged mice. Still, it is unknown if similar epigenetic mechanisms extend to atypical antipsychotics, which are most often prescribed to dementia patients combined with severe neuropsychiatric symptoms. In this study, we report that atypical antipsychotic risperidone also causes increased motor side effect behaviors in aged mice and 5xFAD mice. Histone deacetylase (HDAC) inhibitor Valproic Acid and Entinostat can mitigate the risperidone induced motor side effects. We further showed besides D2R, reduced expression of 5-HT2A, one of the primary atypical antipsychotic targets in the striatum of aged mice that are also mitigated by HDAC inhibitors. Finally, we demonstrate that specific histone acetylation mark H3K27 is hypoacetylated at the 5htr2a and Drd2 promoters in aged mice and can be reversed with HDAC inhibitors. Our work here establishes evidence for a mechanism where aging reduces expression of 5-HT2A and D2R, the key atypical antipsychotic drug targets through epigenetic alteration. HDAC inhibitors can restore 5-HT2A and D2R expression in aged mice and decrease the motor side effects in aged and 5xFAD mice.

Keywords: Alzheimer’s disease; HDAC inhibitors; aging; antipsychotics; epigenetic; motor side effects; neuropsychiatric symptoms; risperidone.

FIGURE 1

Risperidone induces a dose response of motor side effects in aged mice and histone deacetylase (HDAC) inhibitors could prevent the side effects. (A) Motor side effects measured by cataleptic episode in 5 min. Lower dose of RIS at 0.1 mg/kg already showed a significant increase in cataleptic behavior in aged mice but not young mice. However, the higher doses of RIS could cataleptic behavior in both young and aged mice, although more severe in aged mice. (B) General locomotor activity measured by open field. Again, the lower dose of RIS at 0.1 mg/kg displayed a decrease in the distance traveled in aged mice but not in young group. However, higher doses of RIS at 0.5 and 1.0 mg/kg induced the decreased in the distance traveled with a dose respond manner. (C) Co-treatment of lower dose of RIS (0.1 mg/kg) with VPA (400 mg/kg) or MS-275 (10 mg/kg) reduced the duration of catalepsy in aged mice. (D) Lower dose of RIS (0.1 mg/kg) with VPA (400 mg/kg) or MS-275 (10 mg/kg) did mitigate the RIS-induced decrease in locomotor activity in the young but not old mice. Data represent mean ± SEM (n = 6–8/group). *p < 0.05, ^**p < 0.01, ^***p < 0.001, ^****p < 0.0001.

FIGURE 2

Risperidone induces motor side effects in 5xFAD mice and histone deacetylase (HDAC) inhibitor could prevent the side effects. (A) Lower dose of RIS (0.1 mg/kg) induced the cataleptic episode in 5xFAD but not wild type (WT) mice at 12 months of age. Co-treatment of RIS with MS-275 significantly reduced cataleptic episodes of 5xFAD mice. (B) RIS induced reduced general locomotor function in both WT and 5xFAD mice measured by the distance traveled in the open field. However, co-treatment of RIS with MS-275 did not improve general locomotor activity. (C) RIS also effected on motor coordination in 5xFAD mice but not WT controls by decreasing the latency to fall measured the rotarod. Co-treatment of RIS with MS-275 significantly improved motor coordination. Data represent mean ± SEM (n = 8–19/group). ^**p < 0.01, ^***p < 0.001, ^****p < 0.0001.

FIGURE 3

Effects of histone deacetylase (HDAC) inhibitors on 5-HT2A and D2R protein expression in the striatum of young and aged mice. (A, C) 5-HT2A expression was significantly decreased in the striatum in aged mice but not young mice, RIS further induced decreased expression in of 5-HT2A expression in aged mice. Co-treatment of RIS with VPA and MS-275 could restore 5-HT2A expression in aged mice. (B, D) D2R expression was decreased in the striatum in aged mice as compared to young mice administration of both VPA and MS-275 with RIS significantly increased D2R expression in the striatum as compared to Veh and RIS treated aged mice. Data represent mean ± SEM (n = 5). *p < 0.05, ^**p < 0.01, ^***p < 0.001.

FIGURE 4

Effects of histone deacetylase (HDAC) inhibitors on histone acetylation at the 5htr2a and Drd2 gene promoters in the striatum in young and aged mice. (A) No significant differences of H3K27ac binding at the 5htr2a promoter between young and aged group was found, but a significant increase in H3K27ac binding at the 5ht2a promoter in the striatum was found in aged and young mice co-treated with RIS and VPA or MS-275 compared to those treated with RIS alone. (B) H3K27ac binding at the Drd2 promoter was significantly decreased in aged mice as compared to young mice in Veh treated group. However, H3K27ac binding at the Drd2 promoter in the striatum was observed to be significantly increased in aged mice co-treated with RIS and HDAC inhibitors VPA or MS-275 when compared to those treated with Veh alone. Data are presented as mean ± SEM, (n = 5). *p < 0.05, ^**p < 0.01, ^***p < 0.001, ^****p < 0.0001.