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.
Recent advances in research indicate that the development of autism spectrum disorder (ASD) has a strong genetic component. Being able to identify the specific genetic makeup for ASD would allow for better understanding of the disorder and for the development of new treatments. However, ASD remains an extremely complex disorder with more than just one gene related to it. The present review by researchers at Ulm University focuses on the use of mutant mice as animal models in research to find out how genes identified in individuals with ASD affect neurobiological mechanisms and behavior. The mouse model is specifically effective because it can be easily genetically mutated and presents a behavioral phenotype very similar to that of humans. Due to advances in technology, several successful animal models have already been established for known genetic causes of ASD. Successful identification replication studies include Fmr1 mutant mice for FXS, Tcs1 and Tcs2 mutant mice for TSC, and Shank 2 and Shank 3 mutant mice exhibiting autistic-like behaviors and neurobiological phenotypes.
People with a mutated SHANK3 gene often present with delayed or impaired speech, as well as Obsessive Compulsive Disorder-like behaviors; additionally, the SHANK3 mutation is present in some cases of Autism Spectrum Disorder (ASD).The SHANK3 gene assists in neurotransmitter connection, synapse formation, and dendrite spine maturation. In this study by researchers at the University of Texas Southwestern Medical Center, to examine how brain functioning is altered in a way that may lead to ASD, the SHANK3 gene was deleted from a specific region (exon 4-9) of rats’ brains. When evaluated, scientists found that these rats behaviorally: repetitively groomed themselves; had weakened ability to recognize and remember novel and spatial objects; had ultrasonic vocalizations; and socialized abnormally when paired together. Additionally, scientists found that removing the SHANK3 gene from this particular area of the brain reduces levels of SHANK3 in other areas of the brain, as well.
Having the correct gene dosage is imperative to proper brain functioning; a depletion or excess of dosages can lead to multiple neuropsychiatric disorders. Specifically, an abnormal level of the SHANK3 gene is associated with disorders such as Phelan-McDermid Syndrome, autism spectrum disorder, bipolar disorder, and others. SHANK3 assists in neurotransmitter connection, synapse formation, and dendrite spine maturation. In this study by researchers at the Korea University College of Medicine and the Baylor College of Medicine, three specific microRNAs – molecules responsible for gene expression – were evaluated to see if a change in their levels impacts neuronal functioning as well as, specifically, SHANK3 expression. To do this, different proteins were exposed to different amounts of these microRNAs. Ultimately, scientists found that these microRNAs regulated the expression of SHANK3, as well as other protein-encoding genes that interact with SHANK3. Therefore, if SHANK3 is present in the incorrect gene dosage, changing the levels of these microRNAs may help re-regulate it and, in turn, may help to minimize chances of developing a neuropsychiatric disorder associated with SHANK3.