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Regulation of Neural Circuit Development by Cadherin-11 Provides Implications for Autism.

ABSTRACT: Autism spectrum disorder (ASD) is a neurologic condition characterized by alterations in social interaction and communication, and restricted and/or repetitive behaviors. The classical Type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and in autism-specific human tissue. In mice, expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in the cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Both cadherins were expressed in synaptic compartments but only cadherin-8 associated with the excitatory synaptic marker neuroligin-1. Induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed upregulated CDH8 expression levels, but downregulated CDH11. We used Cdh11 knock-out (KO) mice of both sexes to analyze the function of cadherin-11, which could help explain phenotypes observed in autism. Cdh11 ^-/- hippocampal neurons exhibited increased dendritic complexity along with altered neuronal and synaptic activity. Similar to the expression profiles in human tissue, levels of cadherin-8 were significantly elevated in Cdh11 KO brains. Additionally, excitatory synaptic markers neuroligin-1 and postsynaptic density (PSD)-95 were both increased. Together, these results strongly suggest that cadherin-11 is involved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-11 may contribute to the etiology of autism.

SUBMITTER: Frei JA

PROVIDER: S-EPMC8266214 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Interoception involves the processing of sensory information relevant to physiological functioning and is integral to building self-awareness, emotional states, and modulating social behaviors. With the role of interoception in emotional processing and social functioning, there is growing interest in characterizing interoception in autism spectrum disorder (ASD), yet, there are mixed results regarding cardiac interoceptive accuracy in ASD. In this study, we explored the neural basis of cardiac interoception using an fMRI heartbeat-counting task in order to assess neural correlates of primary interoception. We predicted that interoceptive-specific response in the insula, a "hub" for interoception, would be related to ASD symptomatology. We investigated the relationship of insula responses during cardiac interoceptive focus and a self/caregiver-reported autism-related symptom scale (Social Responsiveness Scale-2 (SRS)). Participants included 46 individuals with autism spectrum disorder (ASD) (age 8-54, mean = 19.43 ± 10.68 years) and 54 individuals with typical development for comparison (TC, age 8-53, mean = 21.43 ± 10.41 years). We found no significant difference in cardiac interoceptive accuracy or neural response to cardiac interoception focus in ASD. Several insula subdivisions had a curvilinear relationship to age, peaking in early adulthood. Interoceptive-specific insula response was associated with adult self-report SRS scores; this association differed by diagnostic group and was not present for caregiver-reported scores. This work suggests that (a) there is no global deficit in cardiac interoception in ASD, but integrating interoceptive cues with social information may distinguish individuals with ASD, and (b) there is a developmental trajectory for interoceptive processing in the insula that may be relevant for socio-emotional health. Autism Res 2020, 13: 908-920. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We use internal sensory information from the body, such as signals from the heart, to understand our emotional response to the external world. We measured how accurately people with autism feel their heartbeat and how the brain responds to this type of information. We found no differences between the autism and comparison groups in how the brain senses heartbeats, or in how accurately people feel their heartbeats. However, for people with autism, brain responses while sensing heartbeats were related to social difficulties. This work suggests people with autism may use internal and external information in a different way.

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Regulation of Neural Circuit Development by Cadherin-11 Provides Implications for Autism.

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