Sex Differences in Spatial Learning and Memory in Valproic Acid Rat Model of Autism: Possible Beneficial Role of Exercise Interventions

Abstract

In the current study, we first tried to determine sex differences in spatial learning and memory in the valproic acid (VPA) rat model of autism. Second, the effects of interval training (IT) and continuous training (CT) exercises were examined in male and female offsprings. To induce autism-like animal model, the pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) at the embryonic day 12.5. IT and CT aerobic exercises were started at postnatal day 56. Then, on postnatal days 84–89, a Morris water maze (MWM) test was conducted on the separate groups of offsprings. Aerobic training was performed on a rodent treadmill with 0% slope for 8 weeks, 5 days/week, and 50 min/day. Unlike control animals, VPA-exposed female offspring had a better performance than VPA-exposed male offspring in MWM acquisition. In the case of MWM reference memory, we did not observe a sex difference between VPA-exposed male and VPA-exposed female offspring. Both IT and CT exercises in both control and VPA-exposed male rats significantly improved MWM acquisition. Moreover, both IT and CT exercises significantly improved MWM acquisition in control female rats. In addition, IT exercise (but not CT) significantly improved MWM acquisition in VPA-exposed female offsprings. Both IT and CT exercises in VPA-exposed that male and female offsprings improved the MWM reference memory. In conclusion, our observation demonstrated that prenatal exposure to VPA affects the spatial learning and memory in a sex dependent manner. We have shown that both IT and CT exercises are able to improve cognitive function in healthy and autistic rat offsprings.

An alpha 5-GABAa receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in an animal model for autism

“…Notably, novel object recognition memory deficits were not observed in female VPA rats, indicating sex differences in the performance of VPA rats in the NOR test. These findings agree with reports indicating that VPA-exposed female rats show better performance in some cognitive tasks (Ghahremani et al 2022, Melancia et al 2018.…”

Continuous high-frequency deep brain stimulation of the anterior insula modulates autism-like behavior in a valproic acid-induced rat model

“…These complex combined effects are involved in the modulation of social behaviors and cognitive functions in VPA-exposed rats. Previous studies have shown that VPA-exposed animals and related autism-like models present learning and cognitive dysfunction [ 35 , 46 , 52 ], which may relate to neuronal degeneration and apoptosis in brain areas, including the hippocampus, striatum, and prefrontal cortex [ 53 , 54 ]. Our study also found impaired spatial learning abilities and cognitive rigidity in the VPA-exposed group, but HFS-DBS failed to ameliorate this impairment, possibly due to less bidirectional output from the hippocampus and insula [ 16 ].…”

Effect of intrahippocampal microinjection of VU0155041, a positive allosteric modulator of mGluR4, on long term potentiation in a valproic acid-induced autistic male rat model

“…Between postnatal days 55 and 65, male rats were anesthetized using urethane and positioned in a stereotaxic apparatus for surgery, electrode implantation, and LTP recording. The procedures employed here were akin to those outlined in previous studies conducted by our laboratory ( Mohammadkhani et al, 2022 , Ghahremani et al, 2022 , Safari et al, 2021 ). In essence, under urethane-induced anesthesia through intraperitoneal injection (1.5 g/kg), the rat's head was secured in the stereotaxic apparatus for both surgery and recording.…”

“…This research paper endeavors to shed light on the involvement of hippocampal mGlu4 receptors in PP-DG LTP in the context of autism, using a valproic acid (VPA)-induced autistic rat model. VPA, an antiepileptic drug, has been shown to induce autism-like behaviors and alterations in synaptic plasticity in animal models ( Ghahremani et al, 2022 ), making it a valuable tool for studying the disorder. Clinical research has reported that the maternal usage of VPA, a commonly prescribed antiepileptic drug and mood stabilizer ( Löscher, 2002 ), can impact fetal brain development during pregnancy, leading to various abnormalities in the offspring ( Christensen et al, 2013 ).…”