Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function

Forero, Andrea; Ku, Hsing-Ping; Malpartida, Ana Belen; Wäldchen, Sina; Alhama-Riba, Judit; Kulka, Christina; Aboagye, Benjamin; Norton, William; Young, Andrew M. J.; Ding, Yu; Blum, Robert; Sauer, Markus; Rivero, Olga; Lesch, Klaus‐Peter

doi:10.1016/j.neuropharm.2020.108018

Cited by 18 publications

(12 citation statements)

References 54 publications

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“…Behavioral measures and neural responses were not altered by rs2199430 genotype in the CPT (Go-NoGo task). As the CPT mainly assesses prefrontal functions of cognitive response control that are disturbed in highly impulsive individuals, our result is in accordance with reports that CDH13 −/− mice are predominantly impaired regarding working memory and learning while displaying only subtly increased impulsivity [19,70]. Therefore, future studies that focus on CDH13 in neurodevelopmental disorders should concentrate on the role of CDH13-mediated neuronal outgrowth in attentional networks, such as frontostriatal circuits and hippocampal regions, in both rodent models and human studies.…”

Section: Discussionsupporting

confidence: 92%

“…Therefore, future studies that focus on CDH13 in neurodevelopmental disorders should concentrate on the role of CDH13 -mediated neuronal outgrowth in attentional networks, such as frontostriatal circuits and hippocampal regions, in both rodent models and human studies. For the former, a conditional knockout mouse is already under investigation [ 70 ]; to address the latter, CDH13 +/− and CDH13 −/− human-induced pluripotent cell lines have been created recently [ 71 ] and can be used to investigate the impact of CDH13 on the excitatory-inhibitory balance in neuronal cell models [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

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A Common CDH13 Variant Is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD

Ziegler

Ehlis

Weber

et al. 2021

Genes

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The cell–cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The Rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

A Common CDH13 Variant Is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD

Ziegler

Ehlis

Weber

et al. 2021

Genes

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“…Whereas only 1.5% of 5-HT specific NPCs expressed CDH13, neuronal maturation led to an increase in CDH13 + 5-HT specific cells with about 40% of TPH2 + /ßTUBIII + neurons displaying immunoreactivity for CDH13 + after 8 weeks of neuronal maturation. This time-dependent increase in CDH13 + cells between 5-HT specific neurogenesis and maturation further strengthens the view that CDH13 is involved in the development of the 5-HT system (Forero et al 2020). We conclude that differentiation may generate a mixture of median and dorsal raphe 5-HT specific neurons, and we provide evidence that proteins which have been identified to influence the risk for neurodevelopmental disorders may be studied using this cell system.…”

Section: Discussionsupporting

confidence: 81%

“…During the development of the mouse 5-HT system, CDH13 is enriched in the lateral wing of the dorsal raphe nucleus, whereas the median raphe is spared. CDH13 influences cell density and guides outgrowth of serotonergic neurons to the prefrontal cortex thereby influencing impulsive behavior as well as learning and memory (Forero et al 2020;Forero et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly

et al. 2021

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Human induced pluripotent stem cells (hiPSCs) have revolutionized the generation of experimental disease models, but the development of protocols for the differentiation of functionally active neuronal subtypes with defined specification is still in its infancy. While dysfunction of the brain serotonin (5-HT) system has been implicated in the etiology of various neuropsychiatric disorders, investigation of functional human 5-HT specific neurons in vitro has been restricted by technical limitations. We describe an efficient generation of functionally active neurons from hiPSCs displaying 5-HT specification by modification of a previously reported protocol. Furthermore, 5-HT specific neurons were characterized using high-end fluorescence imaging including super-resolution microscopy in combination with electrophysiological techniques. Differentiated hiPSCs synthesize 5-HT, express specific markers, such as tryptophan hydroxylase 2 and 5-HT transporter, and exhibit an electrophysiological signature characteristic of serotonergic neurons, with spontaneous rhythmic activities, broad action potentials and large afterhyperpolarization potentials. 5-HT specific neurons form synapses reflected by the expression of pre- and postsynaptic proteins, such as Bassoon and Homer. The distribution pattern of Bassoon, a marker of the active zone along the soma and extensions of neurons, indicates functionality via volume transmission. Among the high percentage of 5-HT specific neurons (~ 42%), a subpopulation of CDH13 + cells presumably designates dorsal raphe neurons. hiPSC-derived 5-HT specific neuronal cell cultures reflect the heterogeneous nature of dorsal and median raphe nuclei and may facilitate examining the association of serotonergic neuron subpopulations with neuropsychiatric disorders.

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“…Rplp0 , Ubc , B2m , Gapdh , and Actb2 served as reference genes for normalization of the gene expression. Reactions were run as previously described ( Forero et al, 2020 ). PCR efficiencies for each primer pair were determined with LinRegPCR ( Ruijter et al, 2009 ), using fluorescence raw data extracted from the CFX software.…”

Section: Methodsmentioning

confidence: 99%

Haploinsufficiency of the Attention-Deficit/Hyperactivity Disorder Risk Gene St3gal3 in Mice Causes Alterations in Cognition and Expression of Genes Involved in Myelination and Sialylation

Rivero

Alhama-Riba

et al. 2021

Front. Genet.

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Genome wide association meta-analysis identified ST3GAL3, a gene encoding the beta-galactosidase-alpha-2,3-sialyltransferase-III, as a risk gene for attention-deficit/hyperactivity disorder (ADHD). Although loss-of-function mutations in ST3GAL3 are implicated in non-syndromic autosomal recessive intellectual disability (NSARID) and West syndrome, the impact of ST3GAL3 haploinsufficiency on brain function and the pathophysiology of neurodevelopmental disorders (NDDs), such as ADHD, is unknown. Since St3gal3 null mutant mice display severe developmental delay and neurological deficits, we investigated the effects of partial inactivation of St3gal3 in heterozygous (HET) knockout (St3gal3±) mice on behavior as well as expression of markers linked to myelination processes and sialylation pathways. Our results reveal that male St3gal3 HET mice display cognitive deficits, while female HET animals show increased activity, as well as increased cognitive control, compared to their wildtype littermates. In addition, we observed subtle alterations in the expression of several markers implicated in oligodendrogenesis, myelin formation, and protein sialylation as well as cell adhesion/synaptic target glycoproteins of ST3GAL3 in a brain region- and/or sex-specific manner. Taken together, our findings indicate that haploinsufficiency of ST3GAL3 results in a sex-dependent alteration of cognition, behavior and markers of brain plasticity.

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Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function

Cited by 18 publications

References 54 publications

A Common CDH13 Variant Is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD

A Common CDH13 Variant Is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD

Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly

Haploinsufficiency of the Attention-Deficit/Hyperactivity Disorder Risk Gene St3gal3 in Mice Causes Alterations in Cognition and Expression of Genes Involved in Myelination and Sialylation

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