Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits

Peñagarikano, Olga; Abrahams, Brett S.; Herman, Edward I.; Winden, Kellen D.; Gdalyahu, Amos; Dong, Hongmei; Sonnenblick, Lisa I.; Gruver, Robin; Almajano, Joel; Bragin, Anatol; Golshani, Peyman; Trachtenberg, Joshua T.; Peles, Elior; Geschwind, Daniel H.

doi:10.1016/j.cell.2011.08.040

Cited by 888 publications

(1,090 citation statements)

References 68 publications

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“…40,41 At later developmental stages and in postnatal mice, Cntnap2 is diffusely expressed in the cortex, striatum, thalamus, hypothalamus, periaqueductal grey and superior colliculus. 10,40,41 Additionally, Cntnap2 is strongly expressed in the hippocampal formation in development and in adulthood. 10,41 Recently, Cntnap2 expression has been comprehensively analysed in the Zebra finch brain.…”

Section: Evolution Of Caspr2mentioning

confidence: 99%

“…10,40,41 Additionally, Cntnap2 is strongly expressed in the hippocampal formation in development and in adulthood. 10,41 Recently, Cntnap2 expression has been comprehensively analysed in the Zebra finch brain. 42 Songbirds have the ability to learn and modify their vocalisations, making them a useful model for studying speech learning and sensorimotor integration.…”

Section: Evolution Of Caspr2mentioning

confidence: 99%

“…Cntnap2-null mice also display the presence of ectopic neurons in subcortical white matter (corpus callosum) and mislocalisation of neurons within the six-layer cortex, with significant numbers of upper layer neurons found in deeper cortical layers. 41 Reduced numbers of GABAergic (inhibitory) interneurons were found in the cortex, striatum and hippocampus in comparison to wild-type littermates. 41 However, it is not clear if the reduction in interneurons is a migratory defect or due to other mechanisms such as aberrant neurogenesis or neuronal differentiation.…”

Section: Caspr2 and The Juxtaparanodementioning

confidence: 99%

“…41 Reduced numbers of GABAergic (inhibitory) interneurons were found in the cortex, striatum and hippocampus in comparison to wild-type littermates. 41 However, it is not clear if the reduction in interneurons is a migratory defect or due to other mechanisms such as aberrant neurogenesis or neuronal differentiation.…”

Section: Caspr2 and The Juxtaparanodementioning

confidence: 99%

“…Instead, a reduction of synchronicity of neuronal firing in the somatosensory cortex was detected. 41 These conflicting results may be due to the different experimental setups used, or may reflect developmental differences due to transient vs endogenous knockdown of Cntnap2. The involvement of Caspr2 in synchronicity of neuronal firing is consistent with the observed effects on inhibitory interneuron function given the role they have in coordination of neural network activity.…”

Section: Caspr2 and Neuronal Networkmentioning

confidence: 99%

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Shining a light on CNTNAP2: complex functions to complex disorders

2013

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The genetic basis of complex neurological disorders involving language are poorly understood, partly due to the multiple additive genetic risk factors that are thought to be responsible. Furthermore, these conditions are often syndromic in that they have a range of endophenotypes that may be associated with the disorder and that may be present in different combinations in patients. However, the emergence of individual genes implicated across multiple disorders has suggested that they might share similar underlying genetic mechanisms. The CNTNAP2 gene is an excellent example of this, as it has recently been implicated in a broad range of phenotypes including autism spectrum disorder (ASD), schizophrenia, intellectual disability, dyslexia and language impairment. This review considers the evidence implicating CNTNAP2 in these conditions, the genetic risk factors and mutations that have been identified in patient and population studies and how these relate to patient phenotypes. The role of CNTNAP2 is examined in the context of larger neurogenetic networks during development and disorder, given what is known regarding the regulation and function of this gene. Understanding the role of CNTNAP2 in diverse neurological disorders will further our understanding of how combinations of individual genetic risk factors can contribute to complex conditions.

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Section: Evolution Of Caspr2mentioning

confidence: 99%

Section: Evolution Of Caspr2mentioning

confidence: 99%

Section: Caspr2 and The Juxtaparanodementioning

confidence: 99%

Section: Caspr2 and The Juxtaparanodementioning

confidence: 99%

Section: Caspr2 and Neuronal Networkmentioning

confidence: 99%

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Shining a light on CNTNAP2: complex functions to complex disorders

2013

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Overview of Mouse Models of Autism Spectrum Disorders

Bey

Jiang

2014

CP Pharmacology

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This overview covers many well-characterized mouse models of autism spectrum disorders (ASDs). As there are numerous mouse models of varying design and description in the literature, the models presented here represent examples of genetically engineered models where human genetic evidence supports a causative relationship between the targeted mutation and the behavioral phenotype of the mouse models. As the diagnosis of ASDs is primarily based on behavioral evaluations in humans, we highlight the murine behavioral analogs to human autistic behaviors in different models. However, because the characteristic behaviors of ASDs in humans are in the domains of social interaction, communication, and restricted interests, the translational value of various behavioral assays used in rodents remains a subject of debate. Using genetically engineered mouse models with good construct and face validity will provide a platform for investigating underlying pathophysiological mechanisms and discovering potential therapeutic interventions which will hopefully translate into effective treatments for ASDs. We also illustrate several significant challenges in the field of modeling ASDs in rodents due to the considerable clinical and molecular heterogeneity associated with ASDs in humans.

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From synaptic dysfunction to atypical emotional processing in autism

Reis,

Monteiro

2024

FEBS Letters

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Autism spectrum disorder (ASD) is a complex neurodevelopmental condition mainly characterized by social impairments and repetitive behaviors. Among these core symptoms, a notable aspect of ASD is the presence of emotional complexities, including high rates of anxiety disorders. The inherent heterogeneity of ASD poses a unique challenge in understanding its etiological origins, yet the utilization of diverse animal models replicating ASD traits has enabled researchers to dissect the intricate relationship between autism and atypical emotional processing. In this review, we delve into the general findings about the neural circuits underpinning one of the most extensively researched and evolutionarily conserved emotional states: fear and anxiety. Additionally, we explore how distinct ASD animal models exhibit various anxiety phenotypes, making them a crucial tool for dissecting ASD's multifaceted nature. Overall, to a proper display of fear response, it is crucial to properly process and integrate sensorial and visceral cues to the fear‐induced stimuli. ASD individuals exhibit altered sensory processing, possibly contributing to the emergence of atypical phobias, a prevailing anxiety disorder manifested in this population. Moreover, these individuals display distinctive alterations in a pivotal fear and anxiety processing hub, the amygdala. By examining the neurobiological mechanisms underlying fear and anxiety regulation, we can gain insights into the factors contributing to the distinctive emotional profile observed in individuals with ASD. Such insights hold the potential to pave the way for more targeted interventions and therapies that address the emotional challenges faced by individuals within the autism spectrum.

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Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits

Cited by 888 publications

References 68 publications

Shining a light on CNTNAP2: complex functions to complex disorders

Shining a light on CNTNAP2: complex functions to complex disorders

Overview of Mouse Models of Autism Spectrum Disorders

From synaptic dysfunction to atypical emotional processing in autism

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