Histone deacetylase 1 regulates haloperidol-induced motor side effects in aged mice

Abstract

Background: Antipsychotic drugs prescribed to elderly patients with neuropsychiatric disorders often experience severe extrapyramidal side effects. Previous studies from our group suggest that changes in histone modifications during aging increase the risk for antipsychotic drug side effects, because co-administration of antipsychotics with class 1 histone deacetylase (HDAC) inhibitors could mitigate the severity of motor side effects in aged mice. However, which HDAC subtype contributes to the age-related sensitivity to antipsychotic drug side effects is unknown.

Methods: In this study, we overexpressed histone deacetylase type 1(HDAC1) in the striatum of 3-month-old mice and knocked down HDAC 1 in the striatum of 21-month-old mice by microinjection of AAV9-HDAC1-GFP or AAV9-CRISPR/Cas9-HDAC1-GFP vectors. Four weeks after the viral-vector delivery, the typical antipsychotic drug haloperidol was administered daily for 14 days, followed by motor function assessments through the open field, rotarod, and catalepsy behavioral tests.

Results: Young mice with overexpressed HDAC1 showed increased cataleptic behavior induced by haloperidol administration, which is associated with the increased HDAC1 level in the striatum. In contrast, aged mice with HDAC1 knocked down rescued locomotor activity, motor coordination, and decreased cataleptic behavior induced by haloperidol administration, which is associated with decreased HDAC1 level in the striatum.

Conclusions: Our results suggest that HDAC1 is a critical regulator in haloperidol-induced severe motor side effects in aged mice. Repression of HDAC1 expression in the striatum of aged mice could mitigate typical antipsychotic drug-induced motor side effects.

Keywords: Antipsychotics; Gene editing; Histone deacetylase 1 (HDAC1); Mice; Motor side effects.

Fig. 1.

Schematic Illustration of Experimental Design. Young (3-month-old) mice and aged (21-month-old) mice were injected with either AAV9-HDAC1 or CRISPR-HDAC1 in the dorsal striatum. Mice were allowed one month to enable the virus to transfect and then were administered either haloperidol (0.05 mg/kg) or vehicle (VEH) daily for two weeks. During the last week of injections, mice were performed several behavioral tests to assess motor function 30 mins after haloperidol (HAL) administration. In addition, the striatum was collected for biochemical measurements on the last day of haloperidol administration.

Fig. 2.

Overexpression or Knock Down of HDAC1 in the Striatum of Young or Aged Mice. A: Representative immunoblots displayed a significantly increased HDAC1 protein expression in the striatum of 3-month-aged mice compared to the control group after four weeks of AAV9-HDAC1 transfection. B: Immunoblot quantification of panel A. C: Representative immunoblots displayed a significantly decreased HDAC1 protein expression in the striatum of 21-month-aged mice compared to the control group after four weeks of CRISPR-HDAC1 transfection. D: Immunoblot quantification of panel C.

Fig. 3.

Impact of HDAC 1 Overexpression on Haloperidol-Induced Motor Side Effects in Young Mice. A: Open field test indicated a significant drug effect on general locomotive activity. B: Rotarod behavior test indicated a significant drug and virus effect, but not interaction on motor coordination. C: Catalepsy behavior test showed increased cataleptic behavior in AAV9-GFP+HAL, and AAV9-HDAC1+HAL treated mice compared to AA9-GFP+VEH, and AAV9-HDAC1 +VEH treated mice, however. AAV9-HDAC1+HAL treated mice showed a significant increase in cataleptic episodes. Four independent groups (AAV9-GFP+VEH, AAV9-GFP+HAL, AAV9-HDAC1+VEH, and AAV9-HDAC1 +HAL) of mice were used for this experiment. Data represent mean ± SEM (n = 8/group). *p < 0.05, * *p < 0.01, * ** *p < 0.0001.

Fig. 4.

Impact of HDAC 1 Knock-Down on Haloperidol-Induced Motor Side Effects in Aged Mice. A: Open field test indicated locomotor deficits in scramble sgRNA+HAL mice but not in the CRISPR-HDAC1 +HAL mice. B: Rotarod behavior test also indicated motor coordination deficits in scramble sgRNA +HAL mice, but not CRISPR-HDAC1 +HAL mice. C: Catalepsy behavior test showed increased cataleptic behavior in scramble sgRNA+HAL and CRISPR-HDAC1 +HAL mice compared to scramble sgRNA+VEH and CRISPR-HDAC1 +VEH mice, CRISPR-HDAC1 +HAL mice showed a significant decrease in cataleptic episodes compared to scramble sgRNA+HAL mice. Four independent groups (sgRNA+VEH, sgRNA+HAL, CRISPR-HDAC1 +VEH, and CRISPR-HDAC1 +HAL) of mice were used for this experiment. Data represent mean ± SEM (n = 8–9/group). *p < 0.05, * *p < 0.01, * **p < 0.001 * ** *p < 0.0001