Molecular psychiatry
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Molecular psychiatry · May 2014
CB1 cannabinoid receptor stimulation during adolescence impairs the maturation of GABA function in the adult rat prefrontal cortex.
Converging epidemiological studies indicate that cannabis abuse during adolescence increases the risk of developing psychosis and prefrontal cortex (PFC)-dependent cognitive impairments later in life. However, the mechanisms underlying the adolescent susceptibility to chronic cannabis exposure are poorly understood. Given that the psychoactive constituent of cannabis binds to the CB1 cannabinoid receptor, the present study was designed to determine the impact of a CB1 receptor agonist (WIN) during specific windows of adolescence on the functional maturation of the rat PFC. ⋯ Remarkably, this prefrontal disinhibition could be normalized following a single acute local infusion of the GABA-Aα1 positive allosteric modulator Indiplon, suggesting that adolescent exposure to WIN causes a functional downregulation of GABAergic transmission in the PFC. Accordingly, in vitro recordings from adult rats exposed to WIN during adolescence demonstrate that local prefrontal GABAergic transmission onto layer V pyramidal neurons is markedly reduced to the level seen in the P30-35 PFC. Together, these results indicate that early and mid-adolescence constitute a critical period during which repeated CB1 receptor stimulation is sufficient to elicit an enduring state of PFC network disinhibition resulting from a developmental impairment of local prefrontal GABAergic transmission.
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Molecular psychiatry · Feb 2014
Elevated maternal C-reactive protein and autism in a national birth cohort.
Autism is a complex neuropsychiatric syndrome with a largely unknown etiology. Inflammation during pregnancy may represent a common pathway by which infections and other insults increase risk for the disorder. Hence, we investigated the association between early gestational C-reactive protein (CRP), an established inflammatory biomarker, prospectively assayed in maternal sera, and childhood autism in a large national birth cohort with an extensive serum biobank. ⋯ Increasing maternal CRP levels, classified as a continuous variable, were significantly associated with autism in offspring. For maternal CRP levels in the highest quintile, compared with the lowest quintile, there was a significant, 43% elevated risk. This finding suggests that maternal inflammation may have a significant role in autism, with possible implications for identifying preventive strategies and pathogenic mechanisms in autism and other neurodevelopmental disorders.
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Molecular psychiatry · Feb 2014
Independence of familial transmission of mania and depression: results of the NIMH family study of affective spectrum disorders.
The goal of this study is to investigate the familial transmission of the spectrum of bipolar disorder in a nonclinical sample of probands with a broad range of manifestations of mood disorders. The sample included a total of 447 probands recruited from a clinically enriched community screening and their 2082 adult living and deceased first-degree relatives. A best estimate diagnostic procedure that was based on either direct semistructured interview or structured family history information from multiple informants regarding non-interviewed relatives was employed. ⋯ These findings confirm those of earlier studies of the familial aggregation of bipolar disorder and major depression in the first nonclinical sample, and the largest family study of bipolar disorder in the USA using contemporary nonhierarchical diagnostic criteria for mood and anxiety disorders. The results suggest that these major components of bipolar disorder may represent distinct underlying pathways rather than increasingly severe manifestations of a common underlying diathesis. Therefore, dissection of the broad bipolar phenotype in genetic studies could actually generate new findings that could index novel biologic pathways underlying bipolar disorder.
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Molecular psychiatry · Jan 2014
Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.
Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. ⋯ In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.