Interneurons from Embryonic Development to Cell-Based Therapy

Southwell, Derek G.; Nicholas, Cory R.; Basbaum, Allan I.; Stryker, Michael P.; Kriegstein, Arnold R.; Rubenstein, John L.R.; Alvarez-Buylla, Arturo

doi:10.1126/science.1240622

Cited by 176 publications

(186 citation statements)

References 94 publications

(150 reference statements)

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“…In poststroke neurogenesis, multipotent neural stem cells give rise to immature neurons that migrate long distances and mature in small numbers into neurons with synaptic connections and long‐distance projections 6, 7, 8. This of course resembles both pyramidal neuron development in cortex and inhibitory neuron development in the forebrain 116. Such similarity in tissue repair in stroke to neurodevelopment has prompted suggestions that brain regeneration recapitulates development 117.…”

Section: Regeneration Does Not Recapitulate Developmentmentioning

confidence: 99%

Emergent properties of neural repair: elemental biology to therapeutic concepts

Carmichael

2016

Annals of Neurology

121

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Stroke is the leading cause of adult disability. The past decade has seen advances in basic science research of neural repair in stroke. The brain forms new connections after stroke, which have a causal role in recovery of function. Brain progenitors, including neuronal and glial progenitors, respond to stroke and initiate a partial formation of new neurons and glial cells. The molecular systems that underlie axonal sprouting, neurogenesis, and gliogenesis after stroke have recently been identified. Importantly, tractable drug targets exist within these molecular systems that might stimulate tissue repair. These basic science advances have taken the field to its first scientific milestone; the elemental principles of neural repair in stroke have been identified. The next stages in this field involve understanding how these elemental principles of recovery interact in the dynamic cellular systems of the repairing brain. Emergent principles arise out of the interaction of the fundamental or elemental principles in a system. In neural repair, the elemental principles of brain reorganization after stroke interact to generate higher order and distinct concepts of regenerative brain niches in cellular repair, neuronal networks in synaptic plasticity, and the distinction of molecular systems of neuroregeneration. Many of these emergent principles directly guide the development of new therapies, such as the necessity for spatial and temporal control in neural repair therapy delivery and the overlap of cancer and neural repair mechanisms. This review discusses the emergent principles of neural repair in stroke as they relate to scientific and therapeutic concepts in this field. Ann Neurol 2016;79:895–906

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Section: Regeneration Does Not Recapitulate Developmentmentioning

confidence: 99%

Emergent properties of neural repair: elemental biology to therapeutic concepts

Carmichael

2016

Annals of Neurology

121

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“…Increased excitation in disease states is typically associated with either substantial loss of GABA-ergic interneurons, or dysfunction of interneurons due to loss of their afferent excitatory input and/or changes in their receptors. Imbalances in neuronal excitation and inhibition occur in many neurological and psychiatric disorders (Southwell et al, 2014). These mainly include epilepsy, schizophrenia, neuropathic pain, Alzheimer's disease (AD) and Parkinson's disease (PD) (Shetty and Turner, 2000;Southwell et al, 2014;Tyson and Anderson, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Imbalances in neuronal excitation and inhibition occur in many neurological and psychiatric disorders (Southwell et al, 2014). These mainly include epilepsy, schizophrenia, neuropathic pain, Alzheimer's disease (AD) and Parkinson's disease (PD) (Shetty and Turner, 2000;Southwell et al, 2014;Tyson and Anderson, 2014). Furthermore, certain regions of post-stroke brain and brains exposed to alcohol during the prenatal period also display impaired inhibitory neurotransmission (Daadi et al, 2009;Poulos et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Improved inhibitory neurotransmission may alleviate deficits in these conditions because some loss of certain subclasses of interneurons and/or functional alteration in surviving GABA-ergic interneurons occur in affected brain regions. This perspective has prompted a great interest in examining the usefulness of interneuron cell grafting intervention in regions of the CNS displaying hyperexcitability, deficiency of GABA-ergic interneurons or dysfunction of inhibitory neurotransmission in several preclinical models of neurological and psychiatric diseases (Southwell et al, 2014;Tyson and Anderson, 2014). Particularly, interneuron progenitors from the embryonic ventral telencephalon capable of differentiating into diverse subclasses of interneurons expressing calcium binding proteins such as parvalbumin (PV), calbindin (CBN), calretinin (CR), and neuropeptides such as neuropeptide Y (NPY), somatostatin (SST) have recently received considerable attention.…”

Section: Introductionmentioning

confidence: 99%

“…These progenitors exhibit longdistance tangential migration to populate the cerebral cortex and other forebrain regions (Southwell et al, 2014). Because of their ability to reach distant forebrain areas without the need for a scaffold such as radial glial processes, and their ability to give rise to multiple subclasses of interneurons, medial ganglionic eminence (MGE) progenitors have gained prominence as an excellent source of GABA-ergic progenitors for grafting in preclinical models of neurological disorders exhibiting interneuron deficiency or dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Shetty

Bates

2016

Brain Research

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Several neurological and psychiatric disorders present hyperexcitability of neurons in specific regions of the brain or spinal cord, partly because of some loss and/or dysfunction of gammaamino butyric acid positive (GABA-ergic) inhibitory interneurons. Strategies that enhance inhibitory neurotransmission in the affected brain regions may therefore ease several or most deficits linked to these disorders. This perception has incited a huge interest in testing the efficacy of GABA-ergic interneuron cell grafting into regions of the brain or spinal cord exhibiting hyperexcitability, dearth of GABA-ergic interneurons or impaired inhibitory neurotransmission, using preclinical models of neurological and psychiatric disorders. Interneuron progenitors from the embryonic ventral telencephalon capable of differentiating into diverse subclasses of interneurons have particularly received much consideration because of their ability for dispersion, migration and integration with the host neural circuitry after grafting. The goal of this review is to discuss the premise, scope and advancement of GABA-ergic cell therapy for easing neurological deficits in preclinical models of schizophrenia, chronic neuropathic pain, Alzheimer's disease and Parkinson's disease. As grafting studies in these prototypes have so far utilized either primary cells from the embryonic medial and lateral ganglionic eminences or neural progenitor cells expanded from these eminences as donor material, the proficiency of these cell types is highlighted. Moreover, future studies that are essential prior to considering the possible clinical application of these cells for the above neurological conditions are proposed. Particularly, the need for grafting studies utilizing medial ganglionic eminence-like progenitors generated from human pluripotent stem cells via directed differentiation approaches or somatic cells through direct reprogramming methods are emphasized.

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Suppression of agrin‐22 production and synaptic dysfunction in Cln1^−/− mice

Peng

Pelkey

et al. 2015

Ann Clin Transl Neurol

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ObjectiveOxidative stress in the brain is highly prevalent in many neurodegenerative disorders including lysosomal storage disorders, in which neurodegeneration is a devastating manifestation. Despite intense studies, a precise mechanism linking oxidative stress to neuropathology in specific neurodegenerative diseases remains largely unclear.MethodsInfantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease caused by mutations in the ceroid lipofuscinosis neuronal‐1 (CLN1) gene encoding palmitoyl‐protein thioesterase‐1. Previously, we reported that in the brain of Cln1 −/− mice, which mimic INCL, and in postmortem brain tissues from INCL patients, increased oxidative stress is readily detectable. We used molecular, biochemical, immunohistological, and electrophysiological analyses of brain tissues of Cln1 −/− mice to study the role(s) of oxidative stress in mediating neuropathology.ResultsOur results show that in Cln1 −/− mice oxidative stress in the brain via upregulation of the transcription factor, CCAAT/enhancer‐binding protein‐δ, stimulated expression of serpina1, which is an inhibitor of a serine protease, neurotrypsin. Moreover, in the Cln1 −/− mice, suppression of neurotrypsin activity by serpina1 inhibited the cleavage of agrin (a large proteoglycan), which substantially reduced the production of agrin‐22, essential for synaptic homeostasis. Direct whole‐cell recordings at the nerve terminals of Cln1 −/− mice showed inhibition of Ca2+ currents attesting to synaptic dysfunction. Treatment of these mice with a thioesterase‐mimetic small molecule, N‐tert (Butyl) hydroxylamine (NtBuHA), increased agrin‐22 levels.InterpretationOur findings provide insight into a novel pathway linking oxidative stress with synaptic pathology in Cln1 −/− mice and suggest that NtBuHA, which increased agrin‐22 levels, may ameliorate synaptic dysfunction in this devastating neurodegenerative disease.

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Interneurons from Embryonic Development to Cell-Based Therapy

Cited by 176 publications

References 94 publications

Emergent properties of neural repair: elemental biology to therapeutic concepts

Emergent properties of neural repair: elemental biology to therapeutic concepts

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Suppression of agrin‐22 production and synaptic dysfunction in Cln1^−/− mice

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Interneurons from Embryonic Development to Cell-Based Therapy

Cited by 176 publications

References 94 publications

Emergent properties of neural repair: elemental biology to therapeutic concepts

Emergent properties of neural repair: elemental biology to therapeutic concepts

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Suppression of agrin‐22 production and synaptic dysfunction in Cln1−/− mice

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Suppression of agrin‐22 production and synaptic dysfunction in Cln1^−/− mice