Maternal treatment with aripiprazole prevents the development of a valproic acid-induced autism-like phenotype in juvenile male mice

Abstract

Autism spectrum disorder (ASD) describes a heterogeneous group of neurodevelopmental conditions characterized by deficits in social communication and repetitive behaviors. Aripiprazole (APZ) is an atypical antipsychotic that can safeguard mice against autism-like behavior induced by valproic acid (VPA). In the present study, we examined the effects of maternal treatment with APZ (10 mg/kg) in juvenile mice prenatally exposed to VPA on neurodevelopmental behaviors, social interactions, communication, and working memory, as well as synaptophysin (SYP), synaptosomal-associated protein, 25 kDa (SNAP-25) and microtubule-associated protein 2 (MAP-2) expression in the medial prefrontal cortex (mPFC) and cell viability in the hippocampus. In addition, to evaluate possible APZ interference with the anticonvulsant properties of VPA on pentylenetetrazole (PTZ)-induced seizures were evaluated. Maternal treatment with APZ significantly prevented body weight loss, self-righting, eye-opening, social interactions, social communication, and working memory deficits in mice prenatally exposed to VPA. Additionally, the decrease in the SYP, SNAP-25, and MAP-2 expressions in the mPFC and cell death in the hippocampus was prevented by APZ. Furthermore, APZ (10 mg/kg) did not interfere with the anticonvulsant effect of VPA (15 mg/kg) in animals with PTZ-induced seizures. These findings indicate that maternal treatment with APZ in pregnant mice exposed to VPA protects animals against the ASD-like behavioral phenotype, and this effect may be related, at least in part, to synaptic plasticity and neuronal protection in the PFC and hippocampus. APZ may serve as an effective pharmacological therapeutic target against autistic behaviors in the VPA animal model of ASD, which should be further investigated to verify its clinical relevance.

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

“…For instance, male VPA mice exhibited higher locomotor activity and lower social ability index than females, potentially attributed to increased hippocampal cell atrophy and heightened expression of the 5-HT2A receptor protein in the hippocampus ( 197 ). The VPA exposure in mice or rats can induce several autism-like behaviors related to hippocampal functions, including impairments in spatial learning and memory ( 198 – 206 ), visual recognition memory ( 198 , 203 , 207 – 209 ), working memory ( 208 , 210 ), and emotional regulation ( 199 , 200 , 204 – 206 , 211 – 213 ). It is widely documented that exposure to VPA notably increases levels of the pro-inflammatory markers (IL-1β, TNF-α, IL-6, IFN-γ, IL-17, TGF-β) and reduces levels of the anti-inflammatory marker (IL-10) in the hippocampus ( 199 , 208 , 211 , 213 – 216 ).…”

“…At the same time, increased oxidative stress is accompanied by aberrant mitochondrial electron transport chain enzyme activity, reduced ATP levels, and ultrastructurally destructed mitochondria in the hippocampus ( 198 , 212 ). Exposure of mice or rats to VPA activates mTOR and Notch signaling, which amplifies autophagic deficiency in the hippocampus, characterized by decreased expression levels of Beclin1 and LC3-II and a small number of autophagosomes ( 203 , 210 ). Previous studies evaluating hippocampal excitatory/inhibitory imbalance found that VPA exposure enhanced excitatory glutamatergic and impaired inhibitory GABAergic synaptic transmission, with a decrease in the GABA/glutamate ratio ( 201 , 206 ).…”

“…Data from several studies suggest that chronic treatments with aripiprazole attenuated VPA-induced visual recognition memory ( 207 ) and spatial learning and memory ( 201 ) impairments in mouse/rat offspring with ASD. More importantly, maternal treatment with aripiprazole prevents working memory deficits and hippocampal cell death in juvenile mice exposed to VPA during the prenatal period ( 210 ). Chronic administrations of risperidone improved VPA-induced memory impairment and reductions in hippocampal dendritic spine density, but there was no improvement with acute administrations ( 207 ).…”