Environmental enrichment improves metabolic and behavioral health in the BTBR mouse model of autism

Queen, Nicholas J.; Boardman, Amber A.; Patel, Ripal; Siu, Jason J.; Mo, Xiaokui; Cao, Lei

doi:10.1016/j.psyneuen.2019.104476

Cited by 37 publications

(33 citation statements)

References 60 publications

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“…Data with AMN082 would suggest the use of mGluR7 receptor agonists for treating anxiety (Spooren et al, 2010;Cieślik et al, 2018). Anxiety level is significantly higher in VPA-injected and BTBR mice (Gao et al, 2019;Queen et al, 2020). In agreement with previous results, we found overexpression of mGluR7 alleviates their anxiety-like traits.…”

Section: Discussionsupporting

confidence: 91%

Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice

Wang

Gao

Zhang

et al. 2021

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) is associated with a range of abnormalities pertaining to socialization, communication, repetitive behaviors, and restricted interests. Owing to its complexity, the etiology of ASD remains incompletely understood. The presynaptic G protein-coupled glutamate receptor metabotropic glutamate receptor 7 (mGluR7) is known to be essential for synaptic transmission and is also tightly linked with ASD incidence. Herein, we report that prefrontal cortex (PFC) mGluR7 protein levels were decreased in C57BL/6J mice exposed to valproic acid (VPA) and BTBR T+ Itpr3tf/J mice. The overexpression of mGluR7 in the PFC of these mice using a lentiviral vector was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, anxiety-like, and stereotyped/repetitive behaviors. Intriguingly, patch-clamp recordings revealed that the overexpression of mGluR7 suppressed neuronal excitability by inhibiting action potential discharge frequencies, together with enhanced action potential threshold and increased rheobase. These data offer a scientific basis for the additional study of mGluR7 as a promising therapeutic target in ASD and related neurodevelopmental disorders.

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Section: Discussionsupporting

confidence: 91%

Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice

Wang

Gao

Zhang

et al. 2021

Front. Cell. Neurosci.

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“…It is understood that in utero VPA exposure results in lowered cAMP activity and thus low levels of pCREB (Wu et al, 2017) and consequently may define the low levels of DCX and BDNF in the present study. The loss of DCX in rats treated chronically (upto 90 days) with stimulants (Simchon Tenenbaum et al, 2015) and BDNF in 8-9 week old BTBR mouse (Queen et al, 2020) has been associated with expression of hyperlocomotive traits. In the present study, animals in the VPA group showed the presence of hyperactivity as suggested by the data of number of line crossings and distance traveled.…”

Section: Discussionmentioning

confidence: 99%

Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress

Luhach

Kulkarni²,

Singh

et al. 2021

Autism Research

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology and phenotypes. Phosphodiesterase-1 (PDE1) inhibitors are known to provide benefits in various brain conditions manifesting similar behavioral phenotypes. The pharmacological consequences of vinpocetine administration a PDE1 inhibitor in prenatal-valproic acid (pre-VPA) induced ASD related behavioral phenotypes (social behavior deficits, repetitive behavior, anxiety, hyperlocomotion, and nociception) was assessed. Also, effects on important biochemical markers of neuronal function (DCX-neurogenesis, BDNF-neuronal survival, synapsin-IIa-synaptic transmission, pCREB-neuronal transcription factor), inflammation (interleukin [IL]-6, IL-10, and TNF-α) and oxidative stress (thiobarbituric acid reactive substance [TBARS] and glutathione (GSH) were studied in important brain areas (frontal cortex, cerebral cortex, hippocampus, and striatum). Further, neuronal cell viability was determined in dentate gyrus using Nissl staining. Pre-VPA administration resulted into impaired behavior, brain biochemistry, and neuronal cell viability. Administration of vinpocetine resulted in improvements of pre-VPA impaired social behavior, repetitive behavior, anxiety, locomotion, and nociception. Also, vinpocetine resulted in a significant increase in the levels of BDNF, synapsin-IIa, DCX, pCREB/CREB, IL-10, and GSH along with significant decrease in TNF-α, IL-6, TBARS, number of pyknotic and chromatolytic cells in different brain areas of pre-VPA group. Finally, high association between behavioral parameters and biochemical parameters was observed upon Pearson's correlation analysis. Vinpocetine, a PDE1 inhibitor rectified important behavioral phenotypes related with ASD, possibly by improving neuronal function, brain inflammation and brain oxidative stress. Thus, PDE1 may be a possible target for further understanding ASD. Lay SummaryASD is a brain developmental disorder with a wide array of genetic and environmental factors. Many targets have been identified till date, but a clinical treatment is still afar. The results of this study indicate that vinpocetine administration resulted in amelioration of ASD associated symptomatology in rats, prenatally exposed to VPA. Our research adds a widely expressed brain enzyme PDE1, as a possible novel pharmacological target and opens-up a new line of enquiry for ASD treatment.

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“…In particular, the evidence, confirmed by several studies [ 19 ], showed that there is a real correspondence between the genetic alterations present in autistic subjects and those present in the animal models is fundamental. This made it possible to consider using this animal model for studies that did not focus solely on the psychological and behavioral components, extending the research to the organic and metabolic spheres [ 30 ]. According to these considerations, we performed an initial morphological and subsequent biological evaluation of small intestine samples.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Intestinal Goblet Cells and Changes in Sodium Glucose Transporters Expression: Possible Therapeutic Targets in Autistic BTBR T+Itpr3tf/J Mice

Franco

Bonomini

Borsani

et al. 2021

IJERPH

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Autism spectrum disorder is a neurodevelopmental syndrome with a complicated etiology and could be responsible for disrupted gastrointestinal tract microbiota. The aim of this work was to study intestinal samples from an autistic animal model (BTBR mouse strain) to better describe gastrointestinal alterations. We performed a morphological and biological evaluation of small intestine samples. In terms of morphology, we studied the goblet cells, cells of intestinal mucosal responsible for the production and maintenance of the protective mucous blanket. Alterations in their secretion may indicate an altered rate of mucus synthesis and this is one of the possible causes of gastrointestinal problems. In terms of biological evaluation, impaired regulation of glucose homeostasis regulated by sodium-glucose transporters has been suggested as an important component of obesity and associated comorbidities; therefore, this study analyzed the expression of sodium/glucose transporter-1 and -3 in BTBR mice to better define their role. We demonstrated that, in BTBR mice as compared to C57BL/6J (B6) strain animals: (1) The goblet cells had different protein content in their vesicles and apparently a larger number of Golgi cisternae; (2) the expression and level of sodium/glucose transporters were higher. These findings could suggest new possible targets in autism spectrum disorder to maintain mucus barrier function.

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Environmental enrichment improves metabolic and behavioral health in the BTBR mouse model of autism

Cited by 37 publications

References 60 publications

Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice

Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice

Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress

Involvement of Intestinal Goblet Cells and Changes in Sodium Glucose Transporters Expression: Possible Therapeutic Targets in Autistic BTBR T+Itpr3tf/J Mice

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