Modulation of social deficits and repetitive behaviors in a mouse model of autism: the role of the nicotinic cholinergic system

Wang, Li; Almeida, Luis E.F.; Spornick, Nicholas; Kenyon, Nicholas J.; Kamimura, Sayuri; Khaibullina, Alfia; Nouraie, Mehdi; Quezado, Zenaide M.N.

doi:10.1007/s00213-015-4058-z

Cited by 54 publications

(59 citation statements)

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“…Water intake, mouse weight, and nicotine plasma levels with nicotine doses examined here, have been previously reported in B6 and BTBR mice (Wang et al, 2015). We chose not to evaluate the effects of nicotine on nocifensive behavior in Fmr 1-KO mice because its effects (if any) on social behavioral deficits in the Fmr 1-KO strain have not been characterized.…”

Section: Resultssupporting

confidence: 65%

“…For example, in rats, acute nicotine administration is associated with an U-shaped dose response in complex cognitive tasks that require accurate time perception while in tasks that evaluate response rates, nicotine yields a bell-shaped dose-effect relationship (Popke et al, 2000). We had previously reported that nicotine administered over four weeks at doses used in the present investigation, also yielded non-linear dose-effect relationships on social and repetitive behaviors in the BTBR and B6 mice (Wang et al, 2015). Thus, the findings of a nonlinear pharmacodynamic profile of chronic nicotine on nocifensive behavior in BTBR and B6 mice are in keeping with our previous results and those of others(Picciotto, 2003; Popke et al, 2000).…”

Section: Discussionsupporting

confidence: 53%

“…At higher doses (200 and 400 µg/ml) nicotine decreased hotplate latency, normalizing responsiveness to thermal stimuli, but it decreased cold plate sensitivity, thus accentuating the hyporesponsiveness to noxious cold in BTBR mice. Therefore, these differential responses to the antinociceptive effects of nicotine raise the possibilities that the nicotinic cholinergic system could be altered in ASD and that nicotine, in addition to modulating social deficits and repetitive behaviors (Wang et al, 2015), also modulates the altered nocifensive phenotype in BTBR mice.…”

Section: Discussionmentioning

confidence: 99%

“…Breeding pairs of BTBR T + Itpr3 tf /J (BTBR) and C57BL/6J (B6, control strain for BTBR) mice were purchased from Jackson Laboratory (Bar Harbor, ME) and bred in our animal facility. The BTBR strain has been extensively studied and is known to model the core symptoms of ASD (Brodkin, 2008; McFarlane et al, 2008; Price et al, 2007; Silverman et al, 2013; Silverman et al, 2015; Silverman et al, 2012; Silverman et al, 2010a; Wang et al, 2015). A balanced number of age-matched (8–22 weeks) male and female mice were included in BTBR and B6 studies.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, we sought to determine whether nicotine, an agent that modulates behavior deficits would also modulate altered nociception in the BTBR model. As others and we have shown that the nicotinic cholinergic system modulates social deficits in the BTBR model (Karvat and Kimchi, 2014; Wang et al, 2015), we investigated whether nicotine, which is known to have analgesic effects, would also modulate nocifensive behavior in the BTBR mouse.…”

Section: Introductionmentioning

confidence: 99%

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Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system

et al. 2016

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Caretakers and clinicians alike have long recognized that individuals with autism spectrum disorder (ASD) can have altered sensory processing, which can contribute to its core symptoms. However, the pathobiology of sensory alterations in ASD is poorly understood. Here we examined nocifensive behavior in ASD mouse models, the BTBR T+Itpr3tf/J (BTBR) and the fragile-X mental retardation-1 knockout (Fmr1-KO) mice. We also examined the effects of nicotine on nocifensive behavior given that nicotine, a nicotinic cholinergic receptor (nAChR) agonist that has antinociceptive effects and was shown to improve social deficits and decrease repetitive behaviors in BTBR mice. Compared to respective controls, both BTBR and Fmr1-KO had hyporesponsiveness to noxious thermal stimuli and electrical stimulation of C-sensory fibers, normal responsiveness to electrical stimulation of Aβ- and Aδ-fiber, and hyperresponsiveness to visceral pain after acetic acid intraperitoneal injection. In BTBR, nicotine at lower doses increased, whereas at higher doses, it decreased hotplate latency compared to vehicle. In a significantly different effect pattern, in control mice, nicotine had antinociceptive effects to noxious heat only at the high dose. Interestingly, these nocifensive behavior alterations and differential responses to nicotine antinociceptive effects in BTBR mice were associated with significant downregulation of α3, α4, α5, α7, β2, β3, and β4 nAChR subunits in several cerebral regions both, during embryonic development and adulthood. Taken together, these findings further implicate nAChRs in behaviors alterations in the BTBR model and lend support to the hypothesis that nAChRs may be a target for treatment of behavior deficits and sensory dysfunction in ASD.

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Section: Resultssupporting

confidence: 65%

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system

et al. 2016

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The Role of Nicotinic Receptors in the Attenuation of Autism‐Related Behaviors in a Murine BTBR T + tf/J Autistic Model

Mahmood

Aldhalaan²,

Alshammari

et al. 2020

Autism Research

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Nicotinic receptors are distributed throughout the central and peripheral nervous system. Postmortem studies have reported that some nicotinic receptor subtypes are altered in the brains of autistic people. Recent studies have demonstrated the importance of nicotinic acetylcholine receptors (nAChRs) in the autistic behavior of BTBR T + tf/J mouse model of autism. This study was undertaken to examine the behavioral effects of targeted nAChRs using pharmacological ligands, including nicotine and mecamylamine in BTBR T + tf/J and C57BL/6J mice in a panel of behavioral tests relating to autism. These behavioral tests included the three‐chamber social interaction, self‐grooming, marble burying, locomotor activity, and rotarod test. We examined the effect of various oral doses of nicotine (50, 100, and 400 mcg/mL; po) over a period of 2 weeks in BTBR T + tf/J mouse model. The results indicated that the chronic administration of nicotine modulated sociability and repetitive behavior in BTBR T + tf/J mice while no effects observed in C57BL/6J mice. Furthermore, the nonselective nAChR antagonist, mecamylamine, reversed nicotine effects on sociability and increased repetitive behaviors in BTBR T + tf/J mice. Overall, the findings indicate that the pharmacological modulation of nicotinic receptors is involved in modulating core behavioral phenotypes in the BTBR T + tf/J mouse model. Lay Summary The involvement of brain nicotinic neurotransmission system plays a crucial role in regulating autism‐related behavioral features. In addition, the brain of the autistic‐like mouse model has a low acetylcholine level. Here, we report that nicotine, at certain doses, improved sociability and reduced repetitive behaviors in a mouse model of autism, implicating the potential therapeutic values of a pharmacological intervention targeting nicotinic receptors for autism therapy. Autism Res 2020, 13: 1311–1334. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

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Transmission of behavioral and cognitive impairments across generations in rats subjected to prenatal valproic acid exposure

Taheri,

Joushi,

Esmaeilpour

et al. 2024

Birth Defects Research

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BackgroundAutism spectrum disorder (ASD) represents an inheritable neurodevelopmental condition characterized by social communication deficits and repetitive behaviors. Numerous studies have underscored the significant roles played by genetic and environmental factors in the etiology of ASD, and these factors are known to perpetuate behavioral impairments across generations.ObjectivesThe primary objective of this study was to assess the behavioral and cognitive attributes in the second filial (F2) generation of male and female rats, with a particular focus on those whose parents had been exposed to valproic acid (VPA) during embryonic development.MethodsIn this study, a cohort of 32 male and 32 female rats from the second filial (F2) generation, referred to as Mother.ASD, Father.ASD, or Both.ASD, was examined. These designations indicate whether the mother, father, or both parents had experienced embryonic exposure to valproic acid (600 mg/kg, i.p.). During adolescence, the F2 pups underwent behavioral and cognitive assessments, including open field testing, marble burying, social interaction evaluations, and Morris water maze tasks.ResultsOur data revealed that while both the Mother.ASD and Father.ASD groups, regardless of sex, exhibited elevated anxiety‐like behavior in the open field test. Only the Mother.ASD group displayed repetitive behaviors and deficits in social memory. Additionally, spatial memory impairments were observed in both sexes. These findings highlight the transmission of autistic‐like behaviors in the offspring of Mother.ASD rats from both sexes. Nevertheless, future research endeavors should be more targeted in identifying the specific genes responsible for this transmission.ConclusionIn summary, our findings underscore the transmission of autistic‐like behaviors, including anxiety‐like behavior, repetitive actions, impairments in social interactions, and deficits in memory, to the offspring of the Mother.ASD group, irrespective of their sex.

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Modulation of social deficits and repetitive behaviors in a mouse model of autism: the role of the nicotinic cholinergic system

Cited by 54 publications

References 55 publications

Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system

Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system

The Role of Nicotinic Receptors in the Attenuation of Autism‐Related Behaviors in a Murine BTBR T + tf/J Autistic Model

Transmission of behavioral and cognitive impairments across generations in rats subjected to prenatal valproic acid exposure

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