The Amygdala Excitatory/Inhibitory Balance in a Valproate-Induced Rat Autism Model

Lin, Hui Ching; Gean, Po Wu; Wang, Chao Chuan; Chan, Yun Han; Chen, Po See

doi:10.1371/journal.pone.0055248

Cited by 79 publications

(89 citation statements)

References 74 publications

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“…Therefore to be sure something was not anomalous about our VPA-Hi animals, we examined if in our hands VPA-Hi animals also exhibit autistic-like behaviors similar to what others have reported previously (Schneider and Przewlocki, 2005; Lin et al, 2013). Specifically we examined the social interaction of VPA-Hi and saline control rats with a novel test rat.…”

Section: Resultssupporting

confidence: 55%

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

Banerjee

Sauls

Morales

et al. 2014

Front. Behav. Neurosci.

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Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.

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Section: Resultssupporting

confidence: 55%

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

Banerjee

Sauls

Morales

et al. 2014

Front. Behav. Neurosci.

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“…It should however be noted that the change in EI ratio per se may be a more important observation than the direction of the change, as shifts in EI ratios are highly variable across brain regions28, due to different brain functions, microcircuitry layouts and possibly Neuroligin expression3. Finally, the valproic acid (VPA) animal model of autism exhibits hyper and not hypo-reactive circuits as found in the Nlgn4 KO mice1130. The Nlgn4-KO animal model of autism therefore implies a major loss of synaptic function while the VPA animal model of autism implies a major increase in synaptic function31.…”

Section: Discussionmentioning

confidence: 99%

Nlgn4 knockout induces network hypo-excitability in juvenile mouse somatosensory cortex in vitro

Delattre

Mendola

Meystre

et al. 2013

Sci Rep

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Neuroligins (Nlgns) are postsynaptic cell adhesion molecules that form transynaptic complexes with presynaptic neurexins and regulate synapse maturation and plasticity. We studied the impact of the loss of Nlgn4 on the excitatory and inhibitory circuits in somatosensory cortical slices of juvenile mice by electrically stimulating these circuits using a multi-electrode array and recording the synaptic input to single neurons using the patch-clamp technique. We detected a decreased network response to stimulation in both excitatory and inhibitory circuits of Nlgn4 knock-out animals as compared to wild-type controls, and a decreased excitation-inhibition ratio. These data indicate that Nlgn4 is involved in the regulation of excitatory and inhibitory circuits and contributes to a balanced circuit response to stimulation.

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“…The balance between excitatory and inhibitory neurotransmission (E/I balance) has long been recognized to play a critical role in the development of neuronal circuits, the maturation of the brain and to be impaired in several genetic and teratological models of ASD (Eichler and Meier, 2008; Gibson et al, 2009; Gogolla et al, 2009; Pizzarelli and Cherubini, 2011,2013; Bateup et al, 2013; Lin et al, 2013). Just as glutamate is the major excitatory neurotransmitter in the CNS, gamma aminiobutyric acid (GABA), produced from glutamate, is its major inhibitory neurotransmitter, and an imbalance in the signaling of these two systems is implicated in ASD (Gogolla et al, 2009).…”

Section: Chloride Channel Defects In Asdmentioning

confidence: 99%

Channelopathy pathogenesis in autism spectrum disorders

Schmunk¹,

Gargus²

2013

Front. Genet.

106

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Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects (channelopathies) in the pathogenesis of autism. Indeed, recent genome-wide association, and whole exome- and whole-genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders. Moreover, animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.

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The Amygdala Excitatory/Inhibitory Balance in a Valproate-Induced Rat Autism Model

Cited by 79 publications

References 74 publications

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

Nlgn4 knockout induces network hypo-excitability in juvenile mouse somatosensory cortex in vitro

Channelopathy pathogenesis in autism spectrum disorders

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