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Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations.

ABSTRACT: Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20 years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional studies also demonstrated that the cerebral cortex becomes hyperexcitable with disease progression. In this review, we examine clinical and experimental evidence that cortical development is altered in HD. We also provide preliminary evidence that cortical pyramidal neurons from R6/2 mice, a model of juvenile HD, are hyperexcitable and display dysmorphic processes as early as postnatal day 7. Further, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia, which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD. Finally, we discuss recent treatments aimed at correcting abnormal brain development.

SUBMITTER: Cepeda C

PROVIDER: S-EPMC6801077 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations.

Cepeda Carlos C Oikonomou Katerina D KD Cummings Damian D Barry Joshua J Yazon Vannah-Wila VW Chen Dickson T DT Asai Janelle J Williams Christopher K CK Vinters Harry V HV

Journal of neuroscience research 20190728 12

Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20 years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional s ...[more]

PMID: 31353533

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Project description:BackgroundMany observational studies have found a direct association between adverse in utero, perinatal and postnatal exposures and offspring's depression. These findings are consistent with the 'developmental origins of disease hypothesis'. But no review has comprehensively summarized the roles of these exposures. This review aims to systematically scrutinize the strength of associations between individual prenatal, perinatal, and postnatal exposures and subsequent depression in offspring.MethodsWe conducted a systematic review and meta-analysis to synthesize the literature from the EMBASE, HealthStar, PsychoInfo, and Medline databases since their inception to September 1, 2019. English language articles on population-based prospective cohort studies examining the associations between in utero, perinatal, and postnatal exposures and offspring's depression were searched. Random-effects models were used to calculate pooled estimates, and heterogeneity and sensitivity tests were conducted to explore potential confounders in the relationships of depression and early-life factors. Qualitative analysis was also conducted.ResultsSixty-four prospective cohort studies with 28 exposures studied in the relationships to offspring's depression met inclusion criteria. The meta-analysis found 12 prenatal, perinatal, and postnatal characteristics were associated with an increased risk of depression in offspring: low birth weight, premature birth, small gestational age, maternal education, socioeconomic status, having younger parents (<20 years), having older parents (≥35 years), maternal smoking, paternal smoking, maternal stress, maternal anxiety, and prenatal depression. Heterogeneity and sensitivity tests supported the findings. By and large, study characteristics had no effects on conclusions. Qualitative analyses generally supported the findings of meta-analysis and reported on additional risk factors.ConclusionsThis review provides a robust and comprehensive overview of the lasting psychopathological effects of in utero, perinatal, and postnatal exposures. The findings highlight the need for clinical and public health interventions focusing on the identified risk factors. Large prospective cohort studies are warranted to investigate the combined effects of multiple co-existing early-life exposures.

Dataset Information

Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations.

Publications

Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations.

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