The α7 nicotinic acetylcholine receptor: A mediator of pathogenesis and therapeutic target in autism spectrum disorders and Down syndrome

Deutsch, Stephen I.; Burket, Jessica A.; Urbano, Maria R.; Benson, Andrew D.

doi:10.1016/j.bcp.2015.06.005

Cited by 26 publications

(26 citation statements)

References 56 publications

(187 reference statements)

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“…The α7 nicotinic acetylcholine receptor encoded by the CHRNA7 gene has also been associated with ASD (Deutsch, Urbano, Burket, Herndon, & Winebarger, 2011; Dineley, Pandya, & Yakel, 2015). Due to their role and implication in several pathways (e.g., PI3K/Akt and Wnt), α7 nAChR is considered as powerful therapeutic candidates (Deutsch, Burket, Urbano, & Benson, 2015). …”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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“…These data suggest that genomic instability of the 15q13.3 locus is a rare but important etiological contribution to ASD, in particular, and a heterogeneous array of neurodevelopmental disorders, in general (Miller et al 2009). Nonetheless, the data suggest that correction of defective or insufficient transduction of the ACh/choline signal by the α 7 nAChR during fetal development of the brain and throughout life may be an important therapeutic goal (Deutsch et al 2010(Deutsch et al , 2011(Deutsch et al , 2014(Deutsch et al , 2015.…”

Section: Prevalence and Phenotypic Descriptions Of The 15q133 Deletimentioning

confidence: 97%

“…The development of selective α 7 nAChR agonists and positive allosteric modulators (PAMs) will facilitate design of clinical trials for patients with the 15q13.3 deletion syndrome, in particular, and ASDs and other neurodevelopmental disorders, in general. Importantly, an α 7 nAChR agonist therapeutic intervention may be beneficial in the larger population of persons with ASDs but without evidence of 15q13.3 deletions because of the role that this receptor plays in normal processes of attention, cognition, sociability and neuroprotection (Deutsch et al 2011(Deutsch et al , 2015. Also, functionally deficient α 7 nAChR-mediated neurotransmission may exist in many persons with ASDs and other neurodevelopmental disorders, who do not have diminished expression or expression of a dysfunctional mutated α 7 nAChR subunit.…”

Section: Introductionmentioning

confidence: 96%

“…Also, the 15q13.3 deletion syndrome has encouraged interest in therapeutically targeting the α 7 nAChR to address core symptom domains in ASDs (Deutsch et al 2010(Deutsch et al , 2011(Deutsch et al , 2014(Deutsch et al , 2015. The development of selective α 7 nAChR agonists and positive allosteric modulators (PAMs) will facilitate design of clinical trials for patients with the 15q13.3 deletion syndrome, in particular, and ASDs and other neurodevelopmental disorders, in general.…”

Section: Introductionmentioning

confidence: 97%

“…Although they are an infrequent cause of ASDs, the so-called 15q13.3 deletion syndrome has focused on an etiological contribution of haploinsufficient expression of CHRNA7, the gene coding for the α 7 nicotinic acetylcholine receptor (α 7 nAChR) subunit, and defective transduction of the acetylcholine (ACh) and endogenous choline signals by the α 7 nAChR to ASDs (Deutsch et al 2010(Deutsch et al , 2011(Deutsch et al , 2014(Deutsch et al , 2015Szafranski et al 2010;Hoppman-Chaney et al 2013;Lowther et al 2015); choline, the hydrolytic split product and precursor of ACh, is a selective α 7 nAChR agonist (Deutsch et al 2010(Deutsch et al , 2015. Also, the 15q13.3 deletion syndrome has encouraged interest in therapeutically targeting the α 7 nAChR to address core symptom domains in ASDs (Deutsch et al 2010(Deutsch et al , 2011(Deutsch et al , 2014(Deutsch et al , 2015.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The 15q13.3 deletion syndrome: Deficient α7-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders

Deutsch

Burket

Benson

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Maternal Urinary Fluoride and Child Neurobehavior at Age 36 Months

Malin,

Eckel,

et al. 2024

JAMA Netw Open

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ImportanceRecent studies in Canadian and Mexican populations suggest an association of higher prenatal fluoride exposure with poorer neurobehavioral development, but whether this association holds for US-based populations is unknown.ObjectiveTo examine associations of third trimester maternal urinary fluoride (MUF) with child neurobehavior at age 3 years in the US.Design, Setting, and ParticipantsThis prospective cohort study utilized urine samples archived from 2017 to 2020 and neurobehavioral data assessed from 2020 to 2023 from the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) pregnancy cohort, which consisted of predominately Hispanic women residing in Los Angeles, California. Cohort eligibility criteria at recruitment included being 18 years of age or older, less than 30 weeks’ gestation, and a fluent English or Spanish speaker. Exclusion criteria included having a disability preventing participation or provision of informed consent, being HIV positive or incarcerated, and having a multiple gestation pregnancy. There were 263 mother-child pairs who completed the 3-year study visit. In this analysis, women who reported prenatal smoking were excluded. Data analysis was conducted from October 2022 to March 2024.ExposureSpecific gravity-adjusted MUF (MUFSG), a biomarker of prenatal fluoride exposure.Main Outcomes and MeasuresNeurobehavior was quantified using the Preschool Child Behavior Checklist (CBCL), which included composite scores for Total Problems, Internalizing Problems, and Externalizing Problems. CBCL composite T scores range from 28 to 100. T scores from 60 to 63 are in the borderline clinical range, whereas scores above 63 are in the clinical range. Linear and logistic regression models adjusted for covariates were conducted.ResultsA total of 229 mother-child pairs (mean [SD] maternal age, 29.45 [5.67] years; 116 female children [50.7%] and 113 male children [49.3%]) who had MUFSG measured were included in the study. Median (IQR) MUFSG was 0.76 (0.51-1.19) mg/L, and 32 participants (14.0%) had a Total Problems T score in the borderline clinical or clinical range. A 1-IQR (0.68 mg/L) increase in MUFSG was associated with nearly double the odds of the Total Problems T score being in the borderline clinical or clinical range (odds ratio, 1.83; 95% CI, 1.17-2.86; P = .008), as well as with a 2.29-point increase in T score for the Internalizing Problems composite (B = 2.29; 95% CI, 0.47-4.11; P = .01) and a 2.14-point increase in T score for the Total Problems composite (B = 2.14; 95% CI, 0.29-3.98; P = .02).Conclusions and RelevanceIn this prospective cohort study of mother-child pairs in Los Angeles, California, prenatal fluoride exposure was associated with increased neurobehavioral problems. These findings suggest that there may be a need to establish recommendations for limiting fluoride exposure during the prenatal period.

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The α7 nicotinic acetylcholine receptor: A mediator of pathogenesis and therapeutic target in autism spectrum disorders and Down syndrome

Cited by 26 publications

References 56 publications

Autism throughout genetics: Perusal of the implication of ion channels

Autism throughout genetics: Perusal of the implication of ion channels

The 15q13.3 deletion syndrome: Deficient α7-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders

Maternal Urinary Fluoride and Child Neurobehavior at Age 36 Months

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