This study by researchers from Harvard Medical School examined tactile deficits in four groups of mice harboring different genetic mutations, as well as the relationship between tactile deficits, anxiety, and social behavior. The study also focused on the role of the peripheral nervous system and spinal cord in tactile defects. Mice with mutations in the Mecp2, Gabrb3, Shank3, and Fmr1 genes exhibited tactile hypersensitivity in both a texture-specific novel object recognition test and a tactile prepulse (air puff) inhibition assay. Immunohistochemistry was performed on spinal cord sections from Mecp2 mutant mice. The results of this test suggest that lack of inhibition of low-threshold mechanosensory neurons (LTMR) in the spinal cord results in tactile hypersensitivity for Mecp2 mutants. Next, the effects of the Mecp2 and Gabrb3 mutations on anxiety and sociability was measured using an open-field test, a nest building task, a three-chamber social interaction test, and a tube dominance test. The data indicate that tactile defects resulting from Mecp2 or Gabrb3 deletion during development, but not in adulthood, cause anxiety and social interaction deficits. When Mecp2 was restored in the somatosensory neurons of Mecp-2 null mice, the mice no longer exhibited tactile sensitivity, anxiety-like behavior, or social interaction deficits. Investigating tactile and other sensory impairments further in the future may aid in the development of novel ASD treatments.
The dopamine (DA) neurons of the ventral segmental area (VTA) modify some brain regions that control social and repetitive behaviors. Since SHANK3 coordinates excitatory synaptic function, this study examines the effect of decreased SHANK3 levels in the VTA on social behavior and neuron activity. ShRNA was used to down-regulate SHANK3 in the VTA of mice. A three-chamber social interaction test was used to measure social preference in mice. Whole cell patch clamp recordings were performed on VTA neurons in order to detect excitatory postsynaptic activity. Data indicate that SHANK3 deficiency reduces both social behavior and excitatory transmission to DA neurons in the VTA. However, once-daily PAM-mGluR1 injections normalized DA neuron activity and increased social behavior. Thus, the study identifies mGluR1 modulation as a potential treatment strategy.
Phelan-McDermid syndrome (PMS) is a disorder caused by a deletion in chromosome 22 which results in an impaired functioning of the SHANK3 gene. Individuals with PMS typically have a delay in growth and may have a concurrent diagnosis of autism spectrum disorder (ASD). A study by researchers from the Greenwood Genetic Center, Brown University, and Harvard Medical School aimed to examine the behavior of patients diagnosed with both PMS and ASD and to find any genetic correlations between the two disorders. In this study, the ADI – R and the Vineland II interviews were administered to the parents of 40 children with PMS. Researchers concluded that the size of the deletion on chromosome 22 had a significant, negative correlation to the individual’s symptoms. The results from the Vineland II and ADI – R also suggest that people with PMS are often nonverbal and display persistent deficits in social communication.
Deletions and mutations in SHANK3 gene cause Phelan McDermid Syndrome (PMS) and have also been associated with autism spectrum disorder (ASD) and intellectual disabilities. Using a mouse model of Shank3 deletions, this study examines the hypothesis that deficits of SHANK3 expression impair brain function used in social communication and cognition. A touchscreen test used on the genetically modified mice tested the ability to be habit forming, rule following, and attentive to specific senses like hearing, seeing, and smelling. Results showed that pairwise discrimination associative learning is disrupted in heterozygous Shank3 mice for touchscreen tasks. Mutant mice were slower in visual discrimination and made more task errors. This is the first study that successfully evaluated Shank3 deletion effects using a touchscreen system, thus opening a new pathway to study the neurobiological mechanisms associated with the intellectual effects from genetic deletions and mutations in SHANK3. Further results from the study showed that null mutants (-/-) mice were not able to complete pre-training tasks—a profound deficit in intellectual ability that future studies will aim to investigate further. To read this study by researchers at the UC Davis MIND Institute, click here.
Studies have suggested that behavioral deficiencies in autism spectrum disorder (ASD) can be attributed to abnormal neural connectivity. However, the molecular and neural mechanisms underlying ASD are still unknown. In this study by researchers at Duke University, researchers eliminated exons 4-22 in order to generate Shank3 complete knockout mice. After removing exons 4-22 and establishing knockout mice, differing striatal synapse function, aberrant brain structure, abnormal structural connectivity and behavior similar to that found in ASD were observed. Findings suggest that a lack of Shank3 can impair mGluR5 scaffolding, which can lead to cortico-striatal circuit abnormalities. These abnormalities underlie learning deficiencies and ASD-like behaviors, suggesting causal links between genetic, molecular and circuit systems related to the pathophysiology of ASD. Further research should aim to establish precise links between the molecular changes, behavioral impairments and neurological dysfunction aforementioned.
Fragile X syndrome is a genetic syndrome caused by expanded codon repeat sequences within the FMR1 gene on the X chromosome. The syndrome is associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Previous studies indicate that in the presence of FMR1 premutations, there are decreased zinc (Zn) levels in the brain. A deficit of Zn has been linked predisposing young carriers to increased risk of ASD, ADHD, and other psychopathologies. This study by researchers at UC Davis hypothesized that FMR1 premutation affects Zn homeostasis, bioenergetics, and protein expression of Shank3. To test this hypothesis, researchers used a cross-fostering experiment with mice and a complementary evaluation of Zn and Zn-associated outcomes via breast milk from twenty-five control and five premutation nursing mothers. Results emphasized that FMRP protein expression—and not FMR1 mRNA levels—correlate positively with neurodevelopmental disorders like ASD, ADHD and other psychopathologies. Future studies will be necessary to estimate the correct of Zn needed to avoid the associated risks of the offspring of premutatation mothers.
In this study, Seaver Autism Center researchers compared sensory reactivity in children with Phelan-McDermid Syndrome (PMS) to children with idiopathic ASD (iASD). This study is the first to demonstrate differences in sensory reactivity between children with PMS and iASD, helping to refine the PMS phenotype.
In this study by researchers at the Massachusetts Institute of Technology, researchers aimed to explore the use of a micro-electrode array (MEA) as an assay to help identify the electrical network phenotypes associated with risk genes for autism spectrum disorder (ASD). Researchers characterized local and global network firing in cortical neurons and developed methods to analyze alternations between network active periods (NAP) and network inactive periods (NIP). The Shank3 knockout mouse is an established animal model of ASD. Researchers examined cortical neurons in Shank3 knockout mice and evaluated the electric characteristics of neuronal networks. Results indicated that Shank3 deletion leads to a decrease in neuronal firing activity. Furthermore, researchers identified that decrease in firing activity caused by Shank 3 deletion can be normalized by enhancing excitatory synaptic transmission with an AMPA receptor-positive modulator. Additionally, Shank 3 knockout mice networks produced a shorter NIP during slow network oscillation. This can effectively be normalized through the use of clonazepam. In conclusion, MEA recordings can be used as a means to assess network patterns affected by genes that are associated with ASD.
This study by researchers at the Seaver Autism Center examined the differences in brain function between individuals affected by Phelan-McDermid Syndrome (PMS) and those with idiopathic ASD. The researchers found that children with PMS responded differently to communicative vocal sounds than children with idiopathic ASD, despite both groups possessing similar clinical characteristics.
Currently, the etiology of autism spectrum disorder (ASD) is unclear, and therefore no appropriate “cure” exists. Gene mutations have been found to play a role in the onset of ASD. Mouse models are useful and reliable in studying the cause of disorders such as ASD. The mice strain, Brachury (BTBR) displays a behavioral phenotype very similar to that of ASD. For instance, BTBR mice display behavioral deficits in social functioning, lack of communication ability, and engagement in stereotypic behavior. Although this behavior has been characterized in BTBR mice, the genes and proteins specifically responsible for this ASD-like behavior are unknown. This study focuses on identifying transcriptomic and proteomic brain alterations underlying ASD behavior observed in BTBR mice. Through the use of bioinformatics techniques, researchers at the National Institutes of Health and the University of Antwerp found that in comparison to control mouse models, BTBR mice had various altered genes and proteins (BDNF, Shank3, ERK1, and Caskin1). Additionally, this study identified some distinct altered functional pathways in the ASD-like mice, as compared to the controls. This study emphasizes the importance of bioinformatics as a tool towards further uncovering the biological cause of ASD for the development of novel therapeutic targets.