PV Interneurons: Critical Regulators of E/I Balance for Prefrontal Cortex-Dependent Behavior and Psychiatric Disorders

Frontiers in Neural Circuits, Journal Year: 2018, Volume and Issue: 12

Published: May 16, 2018

Elucidating the prefrontal cortical microcircuit has been challenging, given its role in multiple complex behaviors, including working memory, cognitive flexibility, attention, social interaction, and emotional regulation. Additionally, previous methodological limitations made it difficult to parse out contribution of certain neuronal subpopulations refining representations. However, growing evidence supports a fundamental fast-spiking parvalbumin (PV) GABAergic interneurons regulating pyramidal neuron activity drive appropriate behavioral responses. Further, their function is heavily diminished PFC numerous psychiatric diseases, schizophrenia autism. Previous research demonstrated importance optimal balance excitation inhibition (E/I) circuits maintaining efficiency information processing. Although we are still unraveling mechanisms representation cortex (PFC), E/I seems be crucial, as pharmacological, chemogenetic, optogenetic approaches for disrupting induce impairments range PFC-dependent behaviors. In this review, will explore two key hypotheses. First, PV powerful regulators PFC, help optimize processing supramodal PFC. Second, diminishing sufficient generate an elaborate symptom sequelae corresponding those observed diseases. Then, using framework, speculate on whether circuitry could represent platform development therapeutic interventions disorders function.

Language: Английский

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Common Mechanisms of Excitatory and Inhibitory Imbalance in Schizophrenia and Autism Spectrum Disorders

Current Molecular Medicine, Journal Year: 2015, Volume and Issue: 15(2), P. 146 - 167

Published: March 18, 2015

Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings E/I imbalance may provi de essential insight into etiology these uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, studies that suggest alterations to excitatory/inhibitory circuits keys ASD SCZ pathogenesis. Keywords: Autism, dendritic spine, imbalance, GABAergic interneuron, glutamatergic, mTOR, NMDAR, schizophrenia.

Language: Английский

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Gephyrin: a master regulator of neuronal function?

Nature reviews. Neuroscience, Journal Year: 2014, Volume and Issue: 15(3), P. 141 - 156

Published: Feb. 20, 2014

Language: Английский

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Influence of maternal thyroid hormones during gestation on fetal brain development

Neuroscience, Journal Year: 2015, Volume and Issue: 342, P. 68 - 100

Published: Oct. 9, 2015

Language: Английский

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Effects of air pollution on the nervous system and its possible role in neurodevelopmental and neurodegenerative disorders

Pharmacology & Therapeutics, Journal Year: 2020, Volume and Issue: 210, P. 107523 - 107523

Published: March 9, 2020

Language: Английский

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Increased Functional Connectivity Between Subcortical and Cortical Resting-State Networks in Autism Spectrum Disorder

JAMA Psychiatry, Journal Year: 2015, Volume and Issue: 72(8), P. 767 - 767

Published: June 10, 2015

Individuals with autism spectrum disorder (ASD) exhibit severe difficulties in social interaction, motor coordination, behavioral flexibility, and atypical sensory processing, considerable interindividual variability. This heterogeneous set of symptoms recently led to investigating the presence abnormalities interaction across large-scale brain networks. To date, studies have focused either on constrained sets regions or whole-brain analysis, rather than focusing between networks.To compare intrinsic functional connectivity networks a large sample individuals ASD typically developing control subjects estimate what extent group differences would predict autistic traits reflect different developmental trajectories.We studied 166 male (mean age, 17.6 years; age range, 7-50 years) diagnosed as having DSM-IV-TR Asperger syndrome 193 typical 16.9 6.5-39.4 using resting-state magnetic resonance imaging (MRI). Participants were matched for IQ, head motion, eye status (open closed) MRI scanner. We analyzed data from Autism Brain Imaging Data Exchange (ABIDE), an aggregated 17 centers, made public August 2012.We estimated correlations time courses extracted data-driven method (independent component analysis). Subsequently, we associated estimates strength indexed by Social Responsiveness Scale.Relative participants, showed increased primary subcortical (thalamus basal ganglia) (all t ≥ 3.13, P < .001 corrected). The such connections was severity r 0.21, .0067 In addition, subcortico-cortical decreased entire ≤ -0.09, .012 corrected), although this association significant only participants -0.13, .009 corrected).Our results showing ASD-related impairment cortices suggest that processes they subserve abnormally influence information processing ASD. might contribute occurrence hyposensitivity hypersensitivity top-down regulation behavior.

Language: Английский

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GABAergic Signaling as Therapeutic Target for Autism Spectrum Disorders

Frontiers in Pediatrics, Journal Year: 2014, Volume and Issue: 2

Published: July 8, 2014

γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in adult brain, early postnatal life exerts a depolarizing and excitatory action. This depends on accumulation of chloride inside cell via cation-chloride importer NKCC1, being expression exporter KCC2 very low at birth. The developmentally regulated results extrusion with age shift GABA from to hyperpolarizing direction. action leads intracellular calcium rise through voltage-dependent channels and/or N-methyl-d-aspartate receptors. GABA-mediated signals regulate variety developmental processes proliferation migration, differentiation, synapse maturation, neuronal wiring. Therefore, it is not surprising that some forms neuro-developmental disorders such as autism spectrum (ASDs) are associated alterations GABAergic signaling impairment excitatory/inhibitory balance selective circuits. In this review, we will discuss how changes GABAA-mediated neurotransmission affect several ASDs including Fragile X, Angelman, Rett syndromes. Then, describe various animal models dysfunctions, highlighting their behavioral deficits possibility rescue them by targeting components synapse. particular, cases, reverting polarity responses direction diuretic bumetanide, blocker may have beneficial effects ASDs, thus opening new therapeutic perspectives for treatment these devastating disorders.

Language: Английский

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Glutamate and GABA in autism spectrum disorder—a translational magnetic resonance spectroscopy study in man and rodent models

Translational Psychiatry, Journal Year: 2018, Volume and Issue: 8(1)

Published: May 25, 2018

Abstract Autism spectrum disorder (ASD) is a pervasive neurodevelopmental syndrome with high human and economic burden. The pathophysiology of ASD largely unclear, thus hampering development pharmacological treatments for the core symptoms disorder. Abnormalities in glutamate GABA signaling have been hypothesized to underlie symptoms, may form therapeutic target, but it not known whether these abnormalities are recapitulated humans ASD, as well rodent models We used translational proton magnetic resonance spectroscopy ([1H]MRS) compare levels adult panel six diverse models, encompassing genetic environmental etiologies. [1H]MRS was performed striatum medial prefrontal cortex, humans, mice, rats order allow direct cross-species comparisons specific cortical subcortical brain regions implicated ASD. In concentration reduced this correlated severity social symptoms. were altered either region. reduction striatal mice prenatally exposed valproate, carrying Nlgn3 mutations, other Our findings suggest that glutamate/GABA corticostriatal circuitry be key pathological mechanism ASD; linked alterations neuroligin–neurexin complex.

Language: Английский

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Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder

Frontiers in Neuroscience, Journal Year: 2018, Volume and Issue: 12

Published: May 16, 2018

Autistic Spectrum Disorder (ASD) is a complex neurodevelopmental brain disorder characterized by two core behavioural symptoms, namely impairments in social communication and restricted/repetitive behaviour. The molecular mechanisms underlying ASD are not well understood. Recent, genetic as non-genetic animal models contribute understanding the pathophysiology of ASD, they establish autism-like behaviour mice rats. Among causes, several chromosomal mutations including duplications or deletions could be possible causative factors ASD. In addition, biochemical basis suggests that neurotransmitters, e.g. dopamine (DA), systems serotonin (5-HT), dopamine, gamma-amino butyric acid (GABA), acetylcholine (ACh), glutamate (Glu) histamine (HA) participate onset progression Despite convincible understanding, risperidone aripiprazole only drugs available clinically for improving symptoms following approval Food Drug Administration (FDA). Till date, up to our knowledge there no other drug approved clinical usage specifically symptoms. Many novel candidates classes compounds underway at different phases preclinical development. this review, diversity numerous aetiological alterations variety neurotransmitter generation, release function linked discussed with focus on currently used manage neuropsychiatric related review also highlights development emphasis their pharmacological targets aiming

Language: Английский

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Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study

Psychopharmacology, Journal Year: 2018, Volume and Issue: 235(11), P. 3137 - 3148

Published: Sept. 8, 2018

Standard therapeutic approaches to reduce social anxiety in autistic adults have limited effectiveness. Since 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy shows promise as a treatment for other disorders, blinded, placebo-controlled pilot study was conducted. To explore feasibility and safety of MDMA-assisted reduction fear avoidance that are common the population. Autistic with marked very severe were randomized receive MDMA (75 125 mg, n = 8) or inactive placebo (0 4) during two 8-h sessions (experimental sessions) controlled clinical setting. Double-blinded experimental spaced approximately 1 month apart 3 non-drug following each. The primary outcome change Leibowitz Social Anxiety Scale (LSAS) Total scores from Baseline one after second session. Outcomes measured again six months last Improvement LSAS baseline endpoint significantly greater group compared (P 0.037), placebo-subtracted Cohen's d effect size large (d 1.4, CI − 0.074, 2.874). Change 6-month follow-up showed similar positive results 0.036), 1.1 (CI 0.307, 2.527). remained same continued improve slightly most participants completing active phase. This trial demonstrated rapid durable improvement symptoms psychotherapy. Initial efficacy outcomes support expansion research into larger samples further investigate this novel anxiety. clinicaltrials.gov identifier, NCT02008396

Language: Английский

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