Interneuron Dysfunction in Syndromic Autism: Recent Advances

Takano, Tomoyuki

doi:10.1159/000434638

Cited by 30 publications

(29 citation statements)

References 79 publications

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“…Given the dual and intertwined effects of interneurons on both epileptogenesis and cognitive processes, a more detailed characterization of the natural history of epilepsy and cognitive/comorbidity phenotypes would be needed to firmly conclude which interneuronal deficit is more strongly implicated in these phenotypes. Furthermore, alterations to GABAergic circuits during the development of syndromic autism may be caused or may contribute to a wide variety of neurobiological dysfunctions beyond interneurons and GABA signaling, which, as a whole, may underlie the pathogenesis of ASD …”

Section: Autism Spectrum Disordersmentioning

confidence: 99%

Interneuronopathies and their role in early life epilepsies and neurodevelopmental disorders

2017

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GABAergic interneurons control the neural circuitry and network activity in the brain. The advances in genetics have identified genes that control the development, maturation and integration of GABAergic interneurons and implicated them in the pathogenesis of epileptic encephalopathies or neurodevelopmental disorders. For example, mutations of the Aristaless-Related homeobox X-linked gene (ARX) may result in defective GABAergic interneuronal migration in infants with epileptic encephalopathies like West syndrome (WS), Ohtahara syndrome or X-linked lissencephaly with abnormal genitalia (XLAG). The concept of “interneuronopathy”, i.e. impaired development, migration or function of interneurons, has emerged as a possible etiopathogenic mechanism for epileptic encephalopathies. Treatments that enhance GABA levels, may help seizure control but do not necessarily show disease modifying effect. On the other hand, interneuronopathies can be seen in other conditions in which epilepsy may not be the primary manifestation, such as autism. In this review, we plan to outline briefly the current state of knowledge on the origin, development, and migration and integration of GABAergic interneurons, present neurodevelopmental conditions, with or without epilepsy, that have been associated with interneuronopathies and discuss the evidence linking certain types of interneuronal dysfunction with epilepsy and/or cognitive or behavioral deficits.

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Section: Autism Spectrum Disordersmentioning

confidence: 99%

Interneuronopathies and their role in early life epilepsies and neurodevelopmental disorders

2017

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“…Thus, a complex, dynamic interplay between intrinsic genetic programs and environmental influences shape cortical circuits from early developmental stages into adulthood. Because defects in interneurons and GABAergic signaling have been implicated in neurodevelopmental and neuropsychiatric diseases, including autism (Marín, 2012; Takano, 2015), schizophrenia (Marín, 2012; Lewis, 2014), and epilepsy (Coulter, 2001; Trevelyan et al, 2015), it is of high importance to determine the factors regulating interneuron maturation, as further research in this area will illuminate possible treatments for these clinical problems.…”

Section: Discussionmentioning

confidence: 99%

Neuronal activity controls the development of interneurons in the somatosensory cortex

Babij

Garcia

2016

Front. Biol.

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BACKGROUND Neuronal activity in cortical areas regulates neurodevelopment by interacting with defined genetic programs to shape the mature central nervous system. Electrical activity is conveyed to sensory cortical areas via intracortical and thalamocortical neurons, and includes oscillatory patterns that have been measured across cortical regions. OBJECTIVE In this work, we review the most recent findings about how electrical activity shapes the developmental assembly of functional circuitry in the somatosensory cortex, with an emphasis on interneuron maturation and integration. We include studies on the effect of various neurotransmitters and on the influence of thalamocortical afferent activity on circuit development. We additionally reviewed studies describing network activity patterns. METHODS We conducted an extensive literature search using both the PubMed and Google Scholar search engines. The following keywords were used in various iterations: “interneuron”, “somatosensory”, “development”, “activity”, “network patterns”, “thalamocortical”, “NMDA receptor”, “plasticity”. We additionally selected papers known to us from past reading, and those recommended to us by reviewers and members of our lab. RESULTS We reviewed a total of 132 articles that focused on the role of activity in interneuronal migration, maturation, and circuit development, as well as the source of electrical inputs and patterns of cortical activity in the somatosensory cortex. 79 of these papers included in this timely review were written between 2007 and 2016. CONCLUSIONS Neuronal activity shapes the developmental assembly of functional circuitry in the somatosensory cortical interneurons. This activity impacts nearly every aspect of development and acquisition of mature neuronal characteristics, and may contribute to changing phenotypes, altered transmitter expression, and plasticity in the adult. Progressively changing oscillatory network patterns contribute to this activity in the early postnatal period, although a direct requirement for specific patterns and origins of activity remains to be demonstrated.

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“…Abnormal development and function of interneurons (and specific interneuron subgroups) has been linked to the pathobiology of psychiatric disorders such as schizophrenia, autism and epilepsy 1, 2, 3 . Furthermore, many genes implicated in these brain disorders are strongly enriched in young interneurons 4 .…”

Section: Introductionmentioning

confidence: 99%

Homochronic Transplantation of Interneuron Precursors into Early Postnatal Mouse Brains

Quattrocolo

Isaac

Zhang

et al. 2018

JoVE

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Neuronal fate determination and maturation requires an intricate interplay between genetic programs and environmental signals. However, disentangling the roles of intrinsic vs. extrinsic mechanisms that regulate this differentiation process is a conundrum for all developmental neurobiologists. This issue is magnified for GABAergic interneurons, an incredibly heterogeneous cell population that is born from transient embryonic structures and undergo a protracted migratory phase to disperse throughout the telencephalon. To explore how different brain environments affect interneuron fate and maturation, we developed a protocol for harvesting fluorescently labeled immature interneuron precursors from specific brain regions in newborn mice (P0-P2). At this age, interneuron migration is nearly complete and these cells are residing in their final resting environments with relatively little synaptic integration. Following collection of single cell solutions via flow cytometry, these interneuron precursors are transplanted into P0-P2 wildtype postnatal pups. By performing both homotopic (e.g., cortex-to-cortex) or heterotopic (e.g., cortex-to-hippocampus) transplantations, one can assess how challenging immature interneurons in new brain environments affects their fate, maturation, and circuit integration. Brains can be harvested in adult mice and assayed with a wide variety of posthoc analysis on grafted cells, including immunohistochemical, electrophysiological and transcriptional profiling. This general approach provides investigators with a strategy to assay how distinct brain environments can influence numerous aspects of neuron development and identify if specific neuronal characteristics are primarily driven by hardwired genetic programs or environmental cues.

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Interneuron Dysfunction in Syndromic Autism: Recent Advances

Cited by 30 publications

References 79 publications

Interneuronopathies and their role in early life epilepsies and neurodevelopmental disorders

Interneuronopathies and their role in early life epilepsies and neurodevelopmental disorders

Neuronal activity controls the development of interneurons in the somatosensory cortex

Homochronic Transplantation of Interneuron Precursors into Early Postnatal Mouse Brains

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