Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Daniel A. Nagode, Xiangying Meng, Daniel E. Winkowski, Ed Smith, Hamza Khan-Tareen, Vishnupriya Kareddy, Joseph P.Y. Kao, Patrick O. Kanold
Autism spectrum disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex, we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as "patches" of mostly increased connection probability or strength in the first postnatal week and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as a possible common pathophysiological substrate of deficits in ASD.

Graphical abstract

Teaser

It has been hypothesized that dysfunction of subplate neurons is an early event in autism pathology, but never directly tested. Nagode et al. demonstrate spatially restricted increases in excitatory and inhibitory connectivity to subplate in the VPA autism model. These results provide direct evidence of subplate dysfunction in autism.


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Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Daniel A. Nagode, Xiangying Meng, Daniel E. Winkowski, Ed Smith, Hamza Khan-Tareen, Vishnupriya Kareddy, Joseph P.Y. Kao, Patrick O. Kanold
Autism spectrum disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex, we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as "patches" of mostly increased connection probability or strength in the first postnatal week and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as a possible common pathophysiological substrate of deficits in ASD.

Graphical abstract

Teaser

It has been hypothesized that dysfunction of subplate neurons is an early event in autism pathology, but never directly tested. Nagode et al. demonstrate spatially restricted increases in excitatory and inhibitory connectivity to subplate in the VPA autism model. These results provide direct evidence of subplate dysfunction in autism.


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Visualizing Changes in Cdkn1c Expression Links Early-Life Adversity to Imprint Mis-regulation in Adults

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Mathew Van de Pette, Allifia Abbas, Amelie Feytout, Gráinne McNamara, Ludovica Bruno, Wilson K. To, Andrew Dimond, Alessandro Sardini, Zoe Webster, James McGinty, Eleanor J. Paul, Mark A. Ungless, Paul M.W. French, Dominic J. Withers, Anthony Uren, Anne C. Ferguson-Smith, Matthias Merkenschlager, Rosalind M. John, Amanda G. Fisher
Imprinted genes are regulated according to parental origin and can influence embryonic growth and metabolism and confer disease susceptibility. Here, we designed sensitive allele-specific reporters to non-invasively monitor imprinted Cdkn1c expression in mice and showed that expression was modulated by environmental factors encountered in utero. Acute exposure to chromatin-modifying drugs resulted in de-repression of paternally inherited (silent) Cdkn1c alleles in embryos that was temporary and resolved after birth. In contrast, deprivation of maternal dietary protein in utero provoked permanent de-repression of imprinted Cdkn1c expression that was sustained into adulthood and occurred through a folate-dependent mechanism of DNA methylation loss. Given the function of imprinted genes in regulating behavior and metabolic processes in adults, these results establish imprinting deregulation as a credible mechanism linking early-life adversity to later-life outcomes. Furthermore, Cdkn1c-luciferase mice offer non-invasive tools to identify factors that disrupt epigenetic processes and strategies to limit their long-term impact.

Graphical abstract

Teaser

Van de Pette et al. use sensitive allele-specific reporters to longitudinally image imprinted Cdkn1c expression in mice and show that expression is modulated by environmental factors encountered in utero. These results establish imprinting deregulation as a mechanism linking early-life adversity to later-life outcomes and provide tools to detect imprinting changes in vivo.


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Serotonin Signaling through Prefrontal Cortex 5-HT1A Receptors during Adolescence Can Determine Baseline Mood-Related Behaviors

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Alvaro L. Garcia-Garcia, Qingyuan Meng, Sarah Canetta, Alain M. Gardier, Bruno P. Guiard, Christoph Kellendonk, Alex Dranovsky, E. David Leonardo
Lifelong homeostatic setpoints for mood-related behaviors emerge during adolescence. Serotonin (5-HT) plays an important role in refining the formation of brain circuits during sensitive developmental periods. In rodents, the role of 5-HT1A receptors in general and autoreceptors in particular has been characterized in anxiety. However, less is known about the role of 5-HT1A receptors in depression-related behavior. Here, we show that whole-life suppression of heteroreceptor expression results in a broad depression-like behavioral phenotype accompanied by physiological and cellular changes within medial prefrontal cortex-dorsal raphe proper (mPFC-DRN) circuitry. These changes include increased basal 5-HT in a mPFC that is hyporesponsive to stress and decreased basal 5-HT levels and firing rates in a DRN hyperactivated by the same stressor. Remarkably, loss of heteroreceptors in the PFC at adolescence is sufficient to recapitulate this depression-like behavioral syndrome. Our results suggest that targeting mPFC 5-HT1A heteroreceptors during adolescence in humans may have lifelong ramifications for depression and its treatment.

Graphical abstract

Teaser

Garcia-Garcia et al. use transgenic and viral approaches to demonstrate that signaling through 5-HT1A heteroreceptors in the medial prefrontal cortex during adolescence is critical in establishing baseline mood setpoints.


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Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Inês Milagre, Thomas M. Stubbs, Michelle R. King, Julia Spindel, Fátima Santos, Felix Krueger, Martin Bachman, Anne Segonds-Pichon, Shankar Balasubramanian, Simon R. Andrews, Wendy Dean, Wolf Reik
Global DNA demethylation is an integral part of reprogramming processes in vivo and in vitro, but whether it occurs in the derivation of induced pluripotent stem cells (iPSCs) is not known. Here, we show that iPSC reprogramming involves both global and targeted demethylation, which are separable mechanistically and by their biological outcomes. Cells at intermediate-late stages of reprogramming undergo transient genome-wide demethylation, which is more pronounced in female cells. Global demethylation requires activation-induced cytidine deaminase (AID)-mediated downregulation of UHRF1 protein, and abolishing demethylation leaves thousands of hypermethylated regions in the iPSC genome. Independently of AID and global demethylation, regulatory regions, particularly ESC enhancers and super-enhancers, are specifically targeted for hypomethylation in association with transcription of the pluripotency network. Our results show that global and targeted DNA demethylation are conserved and distinct reprogramming processes, presumably because of their respective roles in epigenetic memory erasure and in the establishment of cell identity.

Graphical abstract

Teaser

Milagre et al. find that two modes of DNA demethylation occur during primary iPSC reprogramming. Global DNA demethylation, more pronounced in female cells, is regulated by AID through UHRF1 and occurs transiently at intermediate-late stages of reprogramming. Targeted DNA demethylation, by contrast, is important in establishing hypomethylation at enhancers of pluripotency genes and occurs similarly in female and male cells.


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Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Shinsuke Ishigaki, Yusuke Fujioka, Yohei Okada, Yuichi Riku, Tsuyoshi Udagawa, Daiyu Honda, Satoshi Yokoi, Kuniyuki Endo, Kensuke Ikenaka, Shinnosuke Takagi, Yohei Iguchi, Naruhiko Sahara, Akihiko Takashima, Hideyuki Okano, Mari Yoshida, Hitoshi Warita, Masashi Aoki, Hirohisa Watanabe, Haruo Okado, Masahisa Katsuno, Gen Sobue
Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio. Normalization of this increased ratio by 4R-T-specific silencing results in recovery of the normal phenotype. These findings suggest a biological link among FUS/SFPQ, tau isoform alteration, and phenotypic expression, which may function in the early pathomechanism of FTLD.

Graphical abstract

Teaser

Ishigaki et al. investigate the functions of Fused in sarcoma (FUS) and its binding partner proline- and glutamine-rich (SFPQ) in regulation of Mapt splicing. The authors show how loss of interaction between FUS and SFPQ causes altered expression ratio of tau isoforms and leads to a neurodegenerative phenotype similar to FTLD. Normalization of this ratio can reduce phenotypic abnormalities in the mouse model of disease.


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Autonomous CaMKII Activity as a Drug Target for Histological and Functional Neuroprotection after Resuscitation from Cardiac Arrest

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Guiying Deng, James E. Orfila, Robert M. Dietz, Myriam Moreno-Garcia, Krista M. Rodgers, Steve J. Coultrap, Nidia Quillinan, Richard J. Traystman, K. Ulrich Bayer, Paco S. Herson
The Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of physiological glutamate signaling, but its role in pathological glutamate signaling (excitotoxicity) remains less clear, with indications for both neuro-toxic and neuro-protective functions. Here, the role of CaMKII in ischemic injury is assessed utilizing our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). CaMKII inhibition (with tatCN21 or tatCN19o) at clinically relevant time points (30 min after resuscitation) greatly reduces neuronal injury. Importantly, CaMKII inhibition also works in combination with mild hypothermia, the current standard of care. The relevant drug target is specifically Ca²⁺-independent "autonomous" CaMKII activity generated by T286 autophosphorylation, as indicated by substantial reduction in injury in autonomy-incompetent T286A mutant mice. In addition to reducing cell death, tatCN19o also protects the surviving neurons from functional plasticity impairments and prevents behavioral learning deficits, even at extremely low doses (0.01 mg/kg), further highlighting the clinical potential of our findings.

Graphical abstract

Teaser

Deng et al. find that CaMKII and its phospho-T286-induced autonomous activity are a promising therapeutic drug target for global cerebral ischemia (induced by cardiac arrest followed by CPR in a mouse model). Pharmacological inhibition or T286A mutation leads to neuroprotection and improves synaptic and functional recovery following cardiac arrest.


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