scholarly journals Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Freddy Zhang ◽  
Benjamin Rein ◽  
Ping Zhong ◽  
Treefa Shwani ◽  
Megan Conrow-Graham ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Social Preference ◽  
Intervention Strategy ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Male Mice ◽  
Behavioral Abnormalities ◽  
Deficient Mice

AbstractAutism spectrum disorder (ASD) is a lifelong developmental disorder characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications and chromatin remodeling, have been implicated in ASD pathology, and provides a promising therapeutic target for ASD. Haploinsufficiency of the SHANK3 gene is causally linked to ASD, so adult (3–5 months old) Shank3-deficient male mice were used in this drug discovery study. We found that combined administration of the class I histone deacetylase inhibitor Romidepsin and the histone demethylase LSD1 inhibitor GSK-LSD1 persistently ameliorated the autism-like social preference deficits, while each individual drug alone was largely ineffective. Another behavioral abnormality in adult Shank3-deficient male mice, heightened aggression, was also alleviated by administration of the dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels of NMDA receptor subunits in prefrontal cortex (PFC) of adult Shank3-deficient mice, resulting in elevated synaptic expression of NMDA receptors and the restoration of NMDAR synaptic function in PFC pyramidal neurons. These results have offered a novel pharmacological intervention strategy for ASD beyond early developmental periods.

scholarly journals Sex-dependent role for EPHB2 in brain development and autism-associated behavior

2021 ◽  
Author(s):  
Ahlem Assali ◽  
Jennifer Y. Cho ◽  
Evgeny Tsvetkov ◽  
Abha R. Gupta ◽  
Christopher W. Cowan
Keyword(s):  
Pyramidal Neurons ◽  
De Novo ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Male Mice ◽  
Sensory Sensitivity ◽  
Hyperactivity Disorder ◽  
Specific Effects ◽  
Layer V

AbstractAutism spectrum disorder (ASD) is characterized by impairments in social communication and interaction and restricted, repetitive behaviors. It is frequently associated with comorbidities, such as attention-deficit hyperactivity disorder, altered sensory sensitivity, and intellectual disability. A de novo nonsense mutation in EPHB2 (Q857X) was discovered in a female patient with ASD [13], revealing EPHB2 as a candidate ASD risk gene. EPHB2 is a receptor tyrosine kinase implicated in axon guidance, synaptogenesis, and synaptic plasticity, positioning it as a plausible contributor to the pathophysiology of ASD and related disorders. In this study, we show that the Q857X mutation produced a truncated protein lacking forward signaling and that global disruption of one EphB2 allele (EphB2+/−) in mice produced several behavioral phenotypes reminiscent of ASD and common associated symptoms. EphB2+/− female, but not male, mice displayed increased repetitive behavior, motor hyperactivity, and learning and memory deficits, revealing sex-specific effects of EPHB2 hypofunction. Moreover, we observed a significant increase in the intrinsic excitability, but not excitatory/inhibitory ratio, of motor cortex layer V pyramidal neurons in EphB2+/− female, but not male, mice, suggesting a possible mechanism by which EPHB2 hypofunction may contribute to sex-specific motor-related phenotypes. Together, our findings suggest that EPHB2 hypofunction, particularly in females, is sufficient to produce ASD-associated behaviors and altered cortical functions in mice.

scholarly journals In utero exposure to endogenous maternal polyclonal anti-Caspr2 antibody leads to behavioral abnormalities resembling autism spectrum disorder in male mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ciara Bagnall-Moreau ◽  
Patricio T. Huerta ◽  
Davide Comoletti ◽  
Andrea La-Bella ◽  
Roseann Berlin ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
In Utero ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
In Utero Exposure ◽  
Male Mice ◽  
Behavioral Abnormalities

scholarly journals Neuroligin3 splice isoforms shape inhibitory synaptic function in the mouse hippocampus

2020 ◽  
Vol 295 (25) ◽  
pp. 8589-8595 ◽  
Author(s):  
Motokazu Uchigashima ◽  
Ming Leung ◽  
Takuya Watanabe ◽  
Amy Cheung ◽  
Timmy Le ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Single Cell ◽  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
Splice Isoforms ◽  
Inhibitory Synaptic Transmission ◽  
Ca1 Pyramidal Neurons

Synapse formation is a dynamic process essential for the development and maturation of the neuronal circuitry in the brain. At the synaptic cleft, trans-synaptic protein–protein interactions are major biological determinants of proper synapse efficacy. The balance of excitatory and inhibitory synaptic transmission (E-I balance) stabilizes synaptic activity, and dysregulation of the E-I balance has been implicated in neurodevelopmental disorders, including autism spectrum disorders. However, the molecular mechanisms underlying the E-I balance remain to be elucidated. Here, using single-cell transcriptomics, immunohistochemistry, and electrophysiology approaches to murine CA1 pyramidal neurons obtained from organotypic hippocampal slice cultures, we investigate neuroligin (Nlgn) genes that encode a family of postsynaptic adhesion molecules known to shape excitatory and inhibitory synaptic function. We demonstrate that the NLGN3 protein differentially regulates inhibitory synaptic transmission in a splice isoform–dependent manner at hippocampal CA1 synapses. We also found that distinct subcellular localizations of the NLGN3 isoforms contribute to the functional differences observed among these isoforms. Finally, results from single-cell RNA-Seq analyses revealed that Nlgn1 and Nlgn3 are the major murine Nlgn genes and that the expression levels of the Nlgn splice isoforms are highly diverse in CA1 pyramidal neurons. Our results delineate isoform-specific effects of Nlgn genes on the E-I balance in the murine hippocampus.

The K63 deubiquitinase CYLD modulates autism-like behaviors and hippocampal plasticity by regulating autophagy and mTOR signaling

2021 ◽  
Vol 118 (47) ◽  
pp. e2110755118
Author(s):  
Elisa Colombo ◽  
Guilherme Horta ◽  
Mona K. Roesler ◽  
Natascha Ihbe ◽  
Stuti Chhabra ◽  
...  
Keyword(s):  
Repetitive Behavior ◽  
Long Term Potentiation ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Mtor Signaling ◽  
Behavioral Profile ◽  
Term Potentiation ◽  
Hippocampal Network ◽  
Deficient Mice

Nondegradative ubiquitin chains attached to specific targets via Lysine 63 (K63) residues have emerged to play a fundamental role in synaptic function. The K63-specific deubiquitinase CYLD has been widely studied in immune cells and lately also in neurons. To better understand if CYLD plays a role in brain and synapse homeostasis, we analyzed the behavioral profile of CYLD-deficient mice. We found that the loss of CYLD results in major autism-like phenotypes including impaired social communication, increased repetitive behavior, and cognitive dysfunction. Furthermore, the absence of CYLD leads to a reduction in hippocampal network excitability, long-term potentiation, and pyramidal neuron spine numbers. By providing evidence that CYLD can modulate mechanistic target of rapamycin (mTOR) signaling and autophagy at the synapse, we propose that synaptic K63-linked ubiquitination processes could be fundamental in understanding the pathomechanisms underlying autism spectrum disorder.

scholarly journals Autism spectrum disorder-like behavior caused by reduced excitatory synaptic transmission in pyramidal neurons of mouse prefrontal cortex

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Sacai ◽  
Kazuto Sakoori ◽  
Kohtarou Konno ◽  
Kenichiro Nagahama ◽  
Honoka Suzuki ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Prefrontal Cortex ◽  
Social Interaction ◽  
Synaptic Transmission ◽  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Spectrum Disorder ◽  
Excitatory Synaptic Transmission ◽  
Layer 2

Abstract Autism spectrum disorder (ASD) is thought to result from deviation from normal development of neural circuits and synaptic function. Many genes with mutation in ASD patients have been identified. Here we report that two molecules associated with ASD susceptibility, contactin associated protein-like 2 (CNTNAP2) and Abelson helper integration site-1 (AHI1), are required for synaptic function and ASD-related behavior in mice. Knockdown of CNTNAP2 or AHI1 in layer 2/3 pyramidal neurons of the developing mouse prefrontal cortex (PFC) reduced excitatory synaptic transmission, impaired social interaction and induced mild vocalization abnormality. Although the causes of reduced excitatory transmission were different, pharmacological enhancement of AMPA receptor function effectively restored impaired social behavior in both CNTNAP2- and AHI1-knockdown mice. We conclude that reduced excitatory synaptic transmission in layer 2/3 pyramidal neurons of the PFC leads to impaired social interaction and mild vocalization abnormality in mice.

scholarly journals Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Carol Eisenberg ◽  
Deepak Subramanian ◽  
Milad Afrasiabi ◽  
Patryk Ziobro ◽  
Jack DeLucia ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Resting Membrane Potential ◽  
Behavioral Deficits ◽  
Ca1 Pyramidal Neurons ◽  
Neuronal Processes ◽  
And Migration ◽  
Y Cells ◽  
Circuit Function ◽  
Deficient Mice

AbstractThe neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit development by regulating numerous crucial neuronal processes, including the maturation of synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the neuropilin 2 (Nrp2) locus contains polymorphisms in patients with autism spectrum disorder (ASD). Nrp2-deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice lacking one or both copies of Nrp2. Immunostaining for interneuron subtypes revealed that Nrp2−/− mice have a reduced number of parvalbumin, somatostatin, and neuropeptide Y cells, mainly in CA1. Whole-cell recordings identified reduced firing and hyperpolarized shift in resting membrane potential in CA1 pyramidal neurons from Nrp2+/− and Nrp2−/− mice compared to age-matched wild-type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2-deficient mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with significantly shorter latency, longer duration, and higher severity in Nrp2−/− compared to Nrp2+/+ animals. Finally, Nrp2+/− and Nrp2−/− but not Nrp2+/+, mice have impaired cognitive flexibility demonstrated by reward-based reversal learning, a task associated with hippocampal circuit function. Together these data demonstrate a broad reduction in interneuron subtypes and compromised inhibition in CA1 of Nrp2−/− mice, which could contribute to the heightened seizure susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype.

scholarly journals Reduced Hippocampal Inhibition and Enhanced Autism-Epilepsy Comorbidity in Mice Lacking Neuropilin 2

2021 ◽  
Author(s):  
Carol Eisenberg ◽  
Deepak Subramanian ◽  
Milad Afrasiabi ◽  
Patryk Ziobro ◽  
Jack DeLucia ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Resting Membrane Potential ◽  
Behavioral Deficits ◽  
Ca1 Pyramidal Neurons ◽  
Neuronal Processes ◽  
And Migration ◽  
Y Cells ◽  
Circuit Function ◽  
Deficient Mice

The neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit development by regulating numerous crucial neuronal processes, including the maturation of synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the neuropilin 2 (Nrp2) locus contains polymorphisms in patients with autism spectrum disorder (ASD). Nrp2 deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice lacking one or both copies of Nrp2. Immunostaining for interneuron subtypes revealed that Nrp2-/- mice have reduced number of parvalbumin, somatostatin and Neuropeptide Y cells, mainly in CA1. Whole cell recordings identified reduced firing and hyperpolarized shift in resting membrane potential in CA1 pyramidal neurons from Nrp2+/- and Nrp2-/- mice compared to age-matched wild-type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2 deficient mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with significantly shorter latency, longer duration and higher severity in Nrp2-/- compared to Nrp2+/+ animals. Finally, Nrp2+/- and Nrp2-/-, but not Nrp2+/+, mice have impaired cognitive flexibility demonstrated by reward-based reversal learning, a task associated with hippocampal circuit function. Together these data demonstrate a broad reduction in interneuron subtypes and compromised inhibition in CA1 of Nrp2-/- mice, which could contribute to the heightened seizure susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype.

scholarly journals Oxytocin ameliorates impaired social behavior in a Chd8 haploinsufficiency mouse model of autism

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Stanislav M. Cherepanov ◽  
Maria Gerasimenko ◽  
Teruko Yuhi ◽  
Kazumi Furuhara ◽  
Chiharu Tsuji ◽  
...  
Keyword(s):  
Social Behavior ◽  
Social Interactions ◽  
Autism Spectrum ◽  
Behavioral Characteristics ◽  
Male Mice ◽  
Gene Encoding ◽  
Behavioral Deficits ◽  
General Anxiety ◽  
Behavioral Abnormalities ◽  
Core Symptoms

Abstract Background Autism spectrum disorder (ASD) is characterized by the core symptoms of impaired social interactions. Increasing evidence suggests that ASD has a strong genetic link with mutations in chromodomain helicase DNA binding protein 8 (CHD8), a gene encoding a chromatin remodeler. It has previously been shown that Chd8 haplodeficient male mice manifest ASD-like behavioral characteristics such as anxiety and altered social behavior. Along with that, oxytocin (OT) is one of the main neuropeptides involved in social behavior. Administration of OT has shown improvement of social behavior in genetic animal models of ASD. The present study was undertaken to further explore behavioral abnormalities of Chd8 haplodeficient mice of both sexes, their link with OT, and possible effects of OT administration. First, we performed a battery of behavioral tests on wild-type and Chd8+/∆SL female and male mice. Next, we measured plasma OT levels and finally studied the effects of intraperitoneal OT injection on observed behavioral deficits. Results We showed general anxiety phenotype in Chd8+/∆SL mice regardless of sex, the depressive phenotype in Chd8+/∆SL female mice only and bidirectional social deficit in female and male mice. We observed decreased level of OT in Chd+/∆SL mice, possibly driven by males. Mice injected by OT demonstrated recovery of social behavior, while reduced anxiety was observed only in male mice. Conclusions Here, we demonstrated that abnormal social behaviors were observed in both male and female Chd8+/∆SL mice. The ability of peripheral OT administration to affect such behaviors along with altered plasma OT levels indicated a possible link between Chd8 + /∆SL and OT in the pathogenesis of ASD as well as the possible usefulness of OT as a therapeutic tool for ASD patients with CHD8 mutations.

scholarly journals The autism-associated gene Scn2a plays an essential role in synaptic stability and learning

2018 ◽  
Author(s):  
Perry WE Spratt ◽  
Roy Ben-Shalom ◽  
Caroline M Keeshen ◽  
Kenneth J Burke ◽  
Rebecca L Clarkson ◽  
...  
Keyword(s):  
Action Potential ◽  
Sodium Channel ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
De Novo ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Cellular Mechanisms ◽  
Behavioral Impairments

SummaryAutism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here, we show NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons, in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic stability, even when NaV1.2 expression was disrupted late in development. Furthermore, we identified behavioral impairments in learning and sociability, paralleling observations in children with SCN2A loss. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms likely underlying circuit and behavioral dysfunction in ASD.

scholarly journals Structural and functional brain-wide alterations in A350V Iqsec2 mutant mice displaying autistic-like behavior

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniela Lichtman ◽  
Eyal Bergmann ◽  
Alexandra Kavushansky ◽  
Nadav Cohen ◽  
Nina S. Levy ◽  
...  
Keyword(s):  
Social Behavior ◽  
Functional Connectivity ◽  
Mouse Model ◽  
Ampa Receptor ◽  
Social Preference ◽  
Autism Spectrum ◽  
Receptor Trafficking ◽  
Anterior Cingulate ◽  
The Impact ◽  
Ampa Receptor Trafficking

AbstractIQSEC2 is an X-linked gene that is associated with autism spectrum disorder (ASD), intellectual disability, and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of IQSEC2 (A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cerebral cortex and hippocampus. Moreover, using a data-driven approach we identify putative alterations in structure–function relations of the frontal, auditory, and visual networks in A350V mice. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three-chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to IQSEC2 mutations.

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