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1.
Mol Psychiatry ; 27(11): 4707-4721, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36123424

ABSTRACT

The precise development of the neocortex is a prerequisite for higher cognitive and associative functions. Despite numerous advances that have been made in understanding neuronal differentiation and cortex development, our knowledge regarding the impact of specific genes associated with neurodevelopmental disorders on these processes is still limited. Here, we show that Taok2, which is encoded in humans within the autism spectrum disorder (ASD) susceptibility locus 16p11.2, is essential for neuronal migration. Overexpression of de novo mutations or rare variants from ASD patients disrupts neuronal migration in an isoform-specific manner. The mutated TAOK2α variants but not the TAOK2ß variants impaired neuronal migration. Moreover, the TAOK2α isoform colocalizes with microtubules. Consequently, neurons lacking Taok2 have unstable microtubules with reduced levels of acetylated tubulin and phosphorylated JNK1. Mice lacking Taok2 develop gross cortical and cortex layering abnormalities. Moreover, acute Taok2 downregulation or Taok2 knockout delayed the migration of upper-layer cortical neurons in mice, and the expression of a constitutively active form of JNK1 rescued these neuronal migration defects. Finally, we report that the brains of the Taok2 KO and 16p11.2 del Het mouse models show striking anatomical similarities and that the heterozygous 16p11.2 microdeletion mouse model displayed reduced levels of phosphorylated JNK1 and neuronal migration deficits, which were ameliorated upon the introduction of TAOK2α in cortical neurons and in the developing cortex of those mice. These results delineate the critical role of TAOK2 in cortical development and its contribution to neurodevelopmental disorders, including ASD.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Neocortex , Protein Serine-Threonine Kinases , Animals , Humans , Mice , Autism Spectrum Disorder/genetics , Autistic Disorder/genetics , Disease Models, Animal , Microtubules/genetics , Microtubules/metabolism , Neocortex/metabolism , Neurogenesis/genetics , Neurogenesis/physiology , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism
2.
Neuroimage ; 257: 119243, 2022 08 15.
Article in English | MEDLINE | ID: mdl-35508216

ABSTRACT

Although initially showing great potential, oxytocin treatment has encountered a translational hurdle in its promise of treating the social deficits of autism. Some debate surrounds the ability of oxytocin to successfully enter the brain, and therefore modify neuroanatomy. Moreover, given the heterogeneous nature of autism, treatment will only amerliorate symptoms in a subset of patients. Therefore, to determine whether oxytocin changes brain circuitry, and whether it does so variably, depending on genotype, we implemented a large randomized, blinded, placebo-controlled, preclinical study on chronic intranasal oxytocin treatment in three different mouse models related to autism with a focus on using neuroanatomical phenotypes to assess and subset treatment response. Intranasal oxytocin (0.6IU) was administered daily, for 28 days, starting at 5 weeks of age to the 16p11.2 deletion, Shank3 (exon 4-9) knockout, and Fmr1 knockout mouse models. Given the sensitivity of structural magnetic resonance imaging (MRI) to the neurological effects of interventions like drugs, along with many other advantages, the mice underwent in vivo longitudinal and high-resolution ex vivo imaging with MRI. The scans included three in vivo T1weighted, 90 um isotropic resolution scans and a T2-weighted, 3D fast spin echo with 40um isotropic resolution ex vivo scan to assess the changes in neuroanatomy using established automated image registration and deformation based morphometry approaches in response to oxytocin treatment. The behavior of the mice was assessed in multiple domains, including social behaviours and repetitive behaviours, among others. Treatment effect on the neuroanatomy did not reach significance, although the pattern of trending effects was promising. No significant effect of treatment was found on social behavior in any of the strains, although a significant effect of treatment was found in the Fmr1 mouse, with treatment normalizing a grooming deficit. No other treatment effect on behavior was observed that survived multiple comparisons correction. Overall, chronic treatment with oxytocin had limited effects on the three mouse models related to autism, and no promising pattern of response susceptibility emerged.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Oxytocin , Administration, Intranasal , Animals , Autism Spectrum Disorder/drug therapy , Autistic Disorder/drug therapy , Disease Models, Animal , Fragile X Mental Retardation Protein , Humans , Mice , Microfilament Proteins/therapeutic use , Nerve Tissue Proteins , Neuroanatomy , Oxytocin/pharmacology , Random Allocation , Social Behavior
3.
Neuroimage ; 226: 117594, 2021 02 01.
Article in English | MEDLINE | ID: mdl-33248253

ABSTRACT

The androgen receptor (AR) is known for masculinization of behavior and brain. To better understand the role that AR plays, mice bearing humanized Ar genes with varying lengths of a polymorphic N-terminal glutamine (Q) tract were created (Albertelli et al., 2006). The length of the Q tract is inversely proporitional to AR activity. Biological studies of the Q tract length may also provide a window into potential AR contributions to sex-biases in disease risk. Here we take a multi-pronged approach to characterizing AR signaling effects on brain and behavior in mice using the humanized Ar Q tract model. We first map effects of Q tract length on regional brain anatomy, and consider if these are modified by gonadal sex. We then test the notion that spatial patterns of anatomical variation related to Q tract length could be organized by intrinsic spatiotemporal patterning of AR gene expression in the mouse brain. Finally, we test influences of Q tract length on four behavioral tests.Altering Q tract length led to neuroanatomical differences in a non-linear dosage-dependent fashion. Gene expression analyses indicated that adult neu- roanatomical changes due to Q tract length are only associated with neurode- velopment (as opposed to adulthood). No significant effect of Q tract length was found on the behavior of the three mouse models. These results indicate that AR activity differentially mediates neuroanatomy and behavior, that AR activity alone does not mediate sex differences, and that neurodevelopmen- tal processes are associated with spatial patterns of volume changes due to Q tract length in adulthood. They also indicate that androgen sensitivity in adulthood is not likely to lead to autism-related behaviors or neuroanatomy, although neurodevelopmental processes may play a role earlier. Further study into sex differences, development, other behaviors, and other sex-specific mech- anisms are needed to better understand AR sensitivity, neurodevelopmental disorders, and the sex difference in their prevalence.


Subject(s)
Behavior, Animal/physiology , Brain/anatomy & histology , Receptors, Androgen/genetics , Sex Characteristics , Animals , Female , Humans , Male , Mice , Polymorphism, Genetic
4.
Mol Psychiatry ; 24(9): 1329-1350, 2019 09.
Article in English | MEDLINE | ID: mdl-29467497

ABSTRACT

Atypical brain connectivity is a major contributor to the pathophysiology of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASDs). TAOK2 is one of several genes in the 16p11.2 microdeletion region, but whether it contributes to NDDs is unknown. We performed behavioral analysis on Taok2 heterozygous (Het) and knockout (KO) mice and found gene dosage-dependent impairments in cognition, anxiety, and social interaction. Taok2 Het and KO mice also have dosage-dependent abnormalities in brain size and neural connectivity in multiple regions, deficits in cortical layering, dendrite and synapse formation, and reduced excitatory neurotransmission. Whole-genome and -exome sequencing of ASD families identified three de novo mutations in TAOK2 and functional analysis in mice and human cells revealed that all the mutations impair protein stability, but they differentially impact kinase activity, dendrite growth, and spine/synapse development. Mechanistically, loss of Taok2 activity causes a reduction in RhoA activation, and pharmacological enhancement of RhoA activity rescues synaptic phenotypes. Together, these data provide evidence that TAOK2 is a neurodevelopmental disorder risk gene and identify RhoA signaling as a mediator of TAOK2-dependent synaptic development.


Subject(s)
Autism Spectrum Disorder/metabolism , Neurodevelopmental Disorders/metabolism , Protein Serine-Threonine Kinases/metabolism , rhoA GTP-Binding Protein/metabolism , Adult , Animals , Anxiety/genetics , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/pathology , Autism Spectrum Disorder/psychology , Child , Cognitive Dysfunction/genetics , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/pathology , Cognitive Dysfunction/psychology , Dendrites/metabolism , Dendrites/pathology , Female , Humans , Interpersonal Relations , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/pathology , Neurodevelopmental Disorders/psychology , Neurogenesis , Phenotype , Phosphorylation , Protein Serine-Threonine Kinases/genetics , Signal Transduction , Synaptic Transmission , Exome Sequencing
5.
Neuroimage ; 173: 411-420, 2018 06.
Article in English | MEDLINE | ID: mdl-29505831

ABSTRACT

Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique in rodent neuroimaging studies. Traditionally, Mn2+ is delivered to animals via a systemic injection; however, this can lead to toxic effects at high doses. Recent studies have shown that subcutaneously implanted mini-osmotic pumps can be used to continuously deliver manganese chloride (MnCl2), and that they produce satisfactory contrast while circumventing many of the toxic side effects. However, neither the time-course of signal enhancement nor the effect of continuous Mn2+ delivery on behaviour, particularly learning and memory, have been well-characterized. Here, we investigated the effect of MnCl2 dose and route of administration on a) spatial learning in the Morris Water Maze and b) tissue signal enhancement in the mouse brain. Even as early as 3 days after pump implantation, infusion of 25-50 mg/kg/day MnCl2 via osmotic pump produced signal enhancement as good as or better than that achieved 24 h after a single 50 mg/kg intraperitoneal injection. Neither route of delivery nor MnCl2 dose adversely affected spatial learning and memory on the water maze. However, especially at higher doses, mice receiving MnCl2 via osmotic pumps developed skin ulceration which limited the imaging window. With these findings, we provide recommendations for route and dose of MnCl2 to use for different study designs.


Subject(s)
Brain/drug effects , Chlorides/administration & dosage , Magnetic Resonance Imaging/methods , Manganese Compounds/administration & dosage , Maze Learning/drug effects , Skin Ulcer/chemically induced , Animals , Chlorides/toxicity , Image Enhancement/methods , Infusion Pumps, Implantable , Male , Mice
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