Cortical interneuron function in autism spectrum condition

Lunden, Jason W; Durens, Madel; Phillips, André W.; Nestor, Michael W.

doi:10.1038/s41390-018-0214-6

Cited by 41 publications

(32 citation statements)

References 140 publications

(207 reference statements)

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“…These behaviors are commonly found in preterm infants, as described above, and in other NDDs, thus supporting the face validity of these models. This is further supported by an extensive body of work showing reduction in GABAergic interneurons or expression of parvalbumin (as distinct from a reduction in cell number) in clinical ASD cases (144)(145)(146) and genetic models of NDDs (147)(148)(149).…”

Section: Moderate/mild Injurymentioning

confidence: 80%

“…A key vulnerable neuronal subpopulation in EoP is interneurons, although it is still unclear which populations are the most vulnerable at which time point and in what regions based on the human and preclinical studies (4,42). Research into neuropathology in NDD, via post-mortem studies and animal models of NDD, also conclusively illustrates changes in interneurons (146). Quite strikingly, in a synaptic protein knockout model of ASD (PTEN KO), interneuron transplantation rescues social behavior deficits (247).…”

Section: Links Between Eop and Neurodevelopmental Diseasesmentioning

confidence: 99%

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Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

2020

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Preterm-born infants frequently suffer from an array of neurological damage, collectively termed encephalopathy of prematurity (EoP). They also have an increased risk of presenting with a neurodevelopmental disorder (e.g., autism spectrum disorder; attention deficit hyperactivity disorder) later in life. It is hypothesized that it is the gray matter injury to the cortex, in addition to white matter injury, in EoP that is responsible for the altered behavior and cognition in these individuals. However, although it is established that gray matter injury occurs in infants following preterm birth, the exact nature of these changes is not fully elucidated. Here we will review the current state of knowledge in this field, amalgamating data from both clinical and preclinical studies. This will be placed in the context of normal processes of developmental biology and the known pathophysiology of neurodevelopmental disorders. Novel diagnostic and therapeutic tactics required integration of this information so that in the future we can combine mechanism-based approaches with patient stratification to ensure the most efficacious and cost-effective clinical practice.

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Section: Moderate/mild Injurymentioning

confidence: 80%

Section: Links Between Eop and Neurodevelopmental Diseasesmentioning

confidence: 99%

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

2020

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“…In the cortex, as a result of their abnormal development, imbalances in glutamatergic excitatory neurons (cExN) and GABAergic inhibitory interneurons (cINs) are thought to contribute to neurodevelopmental disorders including ASD [3, 5, 41]. We, therefore, differentiated iPSCs derived from the UC, and from three family members (the UM, IS, and AP), in parallel into either cExN or cIN neural progenitor cells (NPCs) and/or neurons, to determine if we observed any alterations in the in vitro development of either or both of these neural cell types.…”

Section: Resultsmentioning

confidence: 99%

Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons

et al. 2019

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BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk.MethodsHere, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted.ResultscExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes.ConclusionsWe have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes.

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“…Our results demonstrate an important role for GABAergic 4E-BP2 expression in regulating social behaviors. This is not surprising, given the important function of interneurons in ASD (39) and maintenance of circuit homeostasis, which can affect both excitatory and inhibitory neuronal properties when altered (40,41). Dysregulation of protein synthesis in inhibitory interneurons can engender social behavior deficits, like those observed in the general 4E-BP2 KO mouse (21).…”

Section: Discussionmentioning

confidence: 98%

Inhibitory interneurons mediate autism-associated behaviors via 4E-BP2

Wiebe

Nagpal

Truong

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Translational control plays a key role in regulation of neuronal activity and behavior. Deletion of the translational repressor 4E-BP2 in mice alters excitatory and inhibitory synaptic functions, engendering autistic-like behaviors. The contribution of 4E-BP2-dependent translational control in excitatory and inhibitory neurons and astrocytic cells to these behaviors remains unknown. To investigate this, we generated cell-type-specific conditional 4E-BP2 knockout mice and tested them for the salient features of autism, including repetitive stereotyped behaviors (self-grooming and marble burying), sociability (3-chamber social and direct social interaction tests), and communication (ultrasonic vocalizations in pups). We found that deletion of 4E-BP2 in GABAergic inhibitory neurons, defined by Gad2, resulted in impairments in social interaction and vocal communication. In contrast, deletion of 4E-BP2 in forebrain glutamatergic excitatory neurons, defined by Camk2a, or in astrocytes, defined by Gfap, failed to cause autistic-like behavioral abnormalities. Taken together, we provide evidence for an inhibitory-cell-specific role of 4E-BP2 in engendering autism-related behaviors.

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Cortical interneuron function in autism spectrum condition

Cited by 41 publications

References 140 publications

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons

Inhibitory interneurons mediate autism-associated behaviors via 4E-BP2

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