Tactile stimulation improves neuroanatomical pathology but not behavior in rats prenatally exposed to valproic acid

Raza, Sarah; Harker, Allonna; Richards, Sarah E; Kolb, Bryan; Gibb, Robbin

doi:10.1016/j.bbr.2014.12.055

Cited by 26 publications

(37 citation statements)

References 81 publications

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“…On an anatomical level, marked decreases in the dendritic complexity of the medial prefrontal cortex and orbitofrontal cortex were reported, consistent with substantial evidence of prefrontal cortex-dependent deficits in autism (Prior and Hoffmann, 1990;McEvoy et al, 1993). Thus, the studies carried out by Mychasiuk et al (2012) and Raza et al (2015) support the validity of the oral administration of VPA to pregnant dams as a means of inducing autistic-like anomalies in the developing offspring. Therefore, it is reasonable to conclude that the route of drug administration, in the present study, was similarly effective.…”

Section: Discussionsupporting

confidence: 61%

“…Second, some previous research has shown the occurrence of elevated frequencies of stress-related responses, such as excessive scratching, in rats prenatally exposed to VPA, when tested in anxiety-provoking paradigms (Schneider et al, 2007;Raza et al, 2015). The absence of exaggerated rates of either scratching or stereotyped Atypical play in the VPA rat model of autism Raza et al 713 grooming in the present study suggests that VPA exposure did not increase anxiety in the rats.…”

Section: Discussionmentioning

confidence: 38%

“…Chomiak et al, 2010), whereas in others that did find a sex difference, the effects could be more pronounced in either males (e.g. Schneider et al, 2008) or females (Raza et al, 2015).…”

Section: Introductionmentioning

confidence: 75%

“…Third, examination of the VPA-induced effects utilizing an oral dosing paradigm identical to the one used in the current study showed long-term behavioral and neuroanatomical alterations in rats that are consistent with symptoms of autism (Mychasiuk et al, 2012;Raza et al, 2015). For instance, impaired performance was detected on several behavioral tasks -delayed non-match-to-sample T-maze, skilled reaching, elevated plus maze, and openfield activity -offering interesting parallels to human autism literature, including compromised problem-solving skills, delayed motor skill development, high levels of anxiety, and hyperactivity, respectively (McEvoy et al, 1993;Bellini, 2004;Simonoff et al, 2008;Papadopoulos et al, 2011).…”

Section: Discussionmentioning

confidence: 97%

“…VPA administration followed the protocol described by Raza et al (2015). Pregnant dams were administered VPA orally on gestational day 12.5.…”

Section: Vpa Administrationmentioning

confidence: 99%

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Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats

Raza

Himmler

et al. 2015

Behavioural Pharmacology

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Autism is a severe neurodevelopmental disorder characterized by qualitative impairments in social behavior, communication, and aberrant repetitive behaviors. A major focus of animal models of autism has been to mimic the social deficits of the disorder. The present study assessed whether rats exposed prenatally to valproic acid (VPA) show deficits in social play as juveniles that are consistent with the social deficits observed in autism. Dams were exposed to an acute dose of VPA on gestational day 12.5. Later, the playful interactions and associated ultrasonic vocalizations of the juveniles were examined. It was predicted that VPA-treated rats should play less than the controls. Characteristic of neurobehavioral insult at this early age, the VPA-treated juveniles showed significant increases in the frequency of body shakes and sexual mounting, but played at the same frequency as the controls. However, when playing, they were less likely to use tactics that facilitated bodily contact and vocalized less. These data suggest that prenatal VPA exposure disrupts some aspects of being able to communicate effectively and engage partners in dynamic interactions - deficits that are consistent with those observed in autism.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 38%

“…Chomiak et al, 2010), whereas in others that did find a sex difference, the effects could be more pronounced in either males (e.g. Schneider et al, 2008) or females (Raza et al, 2015).…”

Section: Introductionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 97%

“…VPA administration followed the protocol described by Raza et al (2015). Pregnant dams were administered VPA orally on gestational day 12.5.…”

Section: Vpa Administrationmentioning

confidence: 99%

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Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats

Raza

Himmler

et al. 2015

Behavioural Pharmacology

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Postweaning positive modulation of α5GABAA receptors improves autism‐like features in prenatal valproate rat model in a sex‐specific manner

et al. 2022

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Autism spectrum disorder (ASD), as a common neurodevelopmental disorder that encompasses impairments in social communication and interaction, as well as repetitive and restrictive behavior, still awaits an effective treatment strategy. The involvement of GABAergic neurotransmission, and especially a deficit of GABA A receptors that contain the α5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP-III-022, a positive allosteric modulator (PAM) selective for α5GABAA receptors, in Wistar rats prenatally exposed to valproic acid, as an animal model useful for studying ASD. Postweaning rats of both sexes were treated for 7 days with vehicle or MP-III-022 at two doses pharmacokinetically determined as selective, and thereafter tested in a behavioral battery (social interaction test, elevated plus maze, spontaneous locomotor activity, and standard and reverse Morris water maze). Additional rats were used for establishing a primary neuronal culture and performing calcium imaging, and determination of hippocampal mRNA levels of GABRA5, NKCC1, and KCC2. MP-III-022 prevented impairments in many parameters connected with social, repetitive and restrictive behavioral domains. The lower and higher dose was more effective in males and females, respectively. Intriguingly, MP-III-022 elicited certain changes in control animals similar to those manifested in valproate animals themselves. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, assessed with calcium imaging, and also in expression changes of three genes analyzed. Our data support a role of α5GABAA receptors in pathophysiology of ASD, and suggest a potential application of selective PAMs in its treatment, that needs to be researched in a sex-specific manner. Lay SummaryIn rats prenatally exposed to valproate as a model of autism, a modulator of α5GABAA receptors ameliorated social, repetitive and restrictive impairments, and, intriguingly, elicited certain autism-like changes in control rats. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, and partly in gene expression changes. This shows a role of α5GABAA receptors in pathophysiology of ASD, and a potential application of their selective modulators in its treatment.

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Alteration in social interaction and tactile discrimination of juvenile autistic‐like rats following tactile stimulation and whisker deprivation

et al. 2023

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Introduction: Autism spectrum disorder is a developmental disorder that can affect sensory-motor behaviors in the valproic acid (Val) rodent model of autism. Although whisker deprivation (WD) induces plastic changes in the cortical neurons, tactile stimulation (TS) during the neonatal period may reverse it. Here, we investigate the interaction effects of TS and WD on behavioral and histologic features of barrel cortex neurons in juvenile Val-treated. Methods: Control (CTL, CTL-TS, CTL-WD, and CTL-TS-WD groups) and Val-treated (Val, Val-TS, Val-WD, and Val-TS-WD groups) rats of both sexes were subjected to behavioral tests of social interaction, and novel texture recognition, and Nissl staining. The TS groups were exposed to sensory stimulation for 15 min, three times/day; moreover, all whiskers in the WD groups were trimmed every other day from postnatal days 1 to 21. Results: Both prenatal valproic acid administration and postnatal WD decreased the rats' performance percentage of the Val and CTL-WD groups of both sexes compared with the CTL groups in the social interaction and texture discrimination tests. Following TS, the performance of the Val-TS-WD group increased significantly compared to the Val group (p < .05), whereas the performance of the CTL-TS-WD group rescued to the CTL group. Nissl staining results also revealed the neuron degeneration percentage in the barrel field area of the Val and CTL-WD groups was increased significantly (p < .05) compared with the CTL group. In this regard, TS decreased the neuron degeneration percentage of the Val-TS-WD and the CTL-TS-WD groups, compared with the CTL group, significantly (p < .05). Conclusion:TS in juvenile male and female rats can act as a modulator and compensate for the behavioral and histological consequences of WD and prenatal valproic acid exposure.

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Tactile stimulation improves neuroanatomical pathology but not behavior in rats prenatally exposed to valproic acid

Cited by 26 publications

References 81 publications

Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats

Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats

Postweaning positive modulation of α5GABAA receptors improves autism‐like features in prenatal valproate rat model in a sex‐specific manner

Alteration in social interaction and tactile discrimination of juvenile autistic‐like rats following tactile stimulation and whisker deprivation

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