The Number of Parvalbumin-Expressing Interneurons Is Decreased in the Medial Prefrontal Cortex in Autism

Hashemi, Ezzat; Ariza, Jeanelle; Rogers, Haille; Noctor, Stephen C.; Martínez‐Cerdeño, Verónica

doi:10.1093/cercor/bhw021

Cited by 244 publications

(226 citation statements)

References 108 publications

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“…An assumption that local inhibitory signaling may be affected in the autistic brain is broadly consistent with the prior evidence from the postmortem studies of human brain tissue (Hashemi et al, 2016) as well as with the data obtained in animal models of ASD (for review see, Pizzarelli and Cherubini, 2011). These studies jointly suggest that deficit in GABAergic transmission across multiple brain areas may contribute to diverse behavioral symptoms of ASD.…”

Section: Discussionsupporting

confidence: 85%

Abnormal Size-Dependent Modulation of Motion Perception in Children with Autism Spectrum Disorder (ASD)

et al. 2017

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Excitation/Inhibition (E/I) imbalance in neural networks is now considered among the core neural underpinnings of autism psychopathology. In motion perception at least two phenomena critically depend on E/I balance in visual cortex: spatial suppression (SS), and spatial facilitation (SF) corresponding to impoverished or improved motion perception with increasing stimuli size, respectively. While SS is dominant at high contrast, SF is evident for low contrast stimuli, due to the prevalence of inhibitory contextual modulations in the former, and excitatory ones in the latter case. Only one previous study (Foss-Feig et al., 2013) investigated SS and SF in Autism Spectrum Disorder (ASD). Our study aimed to replicate previous findings, and to explore the putative contribution of deficient inhibitory influences into an enhanced SF index in ASD—a cornerstone for interpretation proposed by Foss-Feig et al. (2013). The SS and SF were examined in 40 boys with ASD, broad spectrum of intellectual abilities (63 < IQ < 127) and 44 typically developing (TD) boys, aged 6–15 years. The stimuli of small (1°) and large (12°) radius were presented under high (100%) and low (1%) contrast conditions. Social Responsiveness Scale and Sensory Profile Questionnaire were used to assess the autism severity and sensory processing abnormalities. We found that the SS index was atypically reduced, while SF index abnormally enhanced in children with ASD. The presence of abnormally enhanced SF in children with ASD was the only consistent finding between our study and that of Foss-Feig et al. While the SS and SF indexes were strongly interrelated in TD participants, this correlation was absent in their peers with ASD. In addition, the SF index but not the SS index correlated with the severity of autism and the poor registration abilities. The pattern of results is partially consistent with the idea of hypofunctional inhibitory transmission in visual areas in ASD. Nonetheless, the absence of correlation between SF and SS indexes paired with a strong direct link between abnormally enhanced SF and autism symptoms in our ASD sample emphasizes the role of the enhanced excitatory influences by themselves in the observed abnormalities in low-level visual phenomena found in ASD.

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Section: Discussionsupporting

confidence: 85%

Abnormal Size-Dependent Modulation of Motion Perception in Children with Autism Spectrum Disorder (ASD)

et al. 2017

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“…Pvalb neuronal loss and/or decreased PV expression has also been observed in post-mortem brains of human ASD patients (Zikopoulos and Barbas, 2013; Stoner et al, 2014; Hashemi et al, 2016) and various ASD mouse models (see Table 1 in Wohr et al, 2015). PV is a calcium-binding protein expressed in specific neurons in the brain (Celio, 1990) and for decades, PV has been used as a reliable marker for a subset of GABAergic inhibitory neurons in the CNS (Celio and Heizmann, 1981).…”

Section: Introductionmentioning

confidence: 88%

Prenatal Valproate Exposure Differentially Affects Parvalbumin-Expressing Neurons and Related Circuits in the Cortex and Striatum of Mice

Lauber

Filice

Schwaller

2016

Front. Mol. Neurosci.

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Autism spectrum disorders (ASD) comprise a number of heterogeneous neurodevelopmental diseases characterized by core behavioral symptoms in the domains of social interaction, language/communication and repetitive or stereotyped patterns of behavior. In utero exposure to valproic acid (VPA) has evolved as a highly recognized rodent ASD model due to the robust behavioral phenotype observed in the offspring and the proven construct-, face- and predictive validity of the model. The number of parvalbumin-immunoreactive (PV+) GABAergic interneurons has been consistently reported to be decreased in human ASD subjects and in ASD animal models. The presumed loss of this neuron subpopulation hereafter termed Pvalb neurons and/or PV deficits were proposed to result in an excitation/inhibition imbalance often observed in ASD. Importantly, loss of Pvalb neurons and decreased/absent PV protein levels have two fundamentally different consequences. Thus, Pvalb neurons were investigated in in utero VPA-exposed male (“VPA”) mice in the striatum, medial prefrontal cortex (mPFC) and somatosensory cortex (SSC), three ASD-associated brain regions. Unbiased stereology of PV+ neurons and Vicia Villosa Agglutinin-positive (VVA+) perineuronal nets, which specifically enwrap Pvalb neurons, was carried out. Analyses of PV protein expression and mRNA levels for Pvalb, Gad67, Kcnc1, Kcnc2, Kcns3, Hcn1, Hcn2, and Hcn4 were performed. We found a ∼15% reduction in the number of PV+ cells and decreased Pvalb mRNA and PV protein levels in the striatum of VPA mice compared to controls, while the number of VVA+ cells was unchanged, indicating that Pvalb neurons were affected at the level of the transcriptome. In selected cortical regions (mPFC, SSC) of VPA mice, no quantitative loss/decrease of PV+ cells was observed. However, expression of Kcnc1, coding for the voltage-gated potassium channel Kv3.1 specifically expressed in Pvalb neurons, was decreased by ∼40% in forebrain lysates of VPA mice. Moreover, hyperpolarization-activated cyclic nucleotide-gated channel (HCN) 1 expression was increased by ∼40% in the same samples from VPA mice. We conclude that VPA leads to alterations that are brain region- and gene-specific including Pvalb, Kcnc1, and Hcn1 possibly linked to homeostatic mechanisms. Striatal PV down-regulation appears as a common feature in a subset of genetic (Shank3B-/-) and environmental ASD models.

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“…This increase is limited to neurons, as the difference in glial number is insignificant [77]. The number of parvalbumin-immunoreactive interneurons, but not those expressing calbindin or calretinin, is decreased in the medial PFC [148], which was recently confirmed to be due to fewer chandelier interneurons [12]. …”

Section: Neuropathology Of Asd: Recent Findings From Human Studiesmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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The Number of Parvalbumin-Expressing Interneurons Is Decreased in the Medial Prefrontal Cortex in Autism

Cited by 244 publications

References 108 publications

Abnormal Size-Dependent Modulation of Motion Perception in Children with Autism Spectrum Disorder (ASD)

Abnormal Size-Dependent Modulation of Motion Perception in Children with Autism Spectrum Disorder (ASD)

Prenatal Valproate Exposure Differentially Affects Parvalbumin-Expressing Neurons and Related Circuits in the Cortex and Striatum of Mice

Autism spectrum disorder: neuropathology and animal models

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