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.
It is currently unknown whether the neurobiological findings present in young adults with autism spectrum disorder (ASD) are also present in older adults. Autism spectrum disorder (ASD) is a neurodevelopmental disorder involving deficits in information processing. Inhibitory and excitatory synapses are essential in information processing in the brain. Furthermore, previous studies have found that ASD likely arises from an imbalance between inhibitory and excitatory synaptic transmission. However, due to a lack of studies of ASD in old age, synaptic structures in adults are poorly understood. In a study by researchers at Shanxi Provincial People’s Hospital, researchers compared the morphology and synaptic function of excitatory synapses in aged mice with low level sociability (BTBR) to mice with high level sociability (control mice). Researchers labeled pre-synaptic protein and post-synaptic protein Shank3. Shank3 is found in excitatory synapses and is highly associated with ASD. Through image analysis, researchers then quantified and noted the colocalization of pre- and post- synapses in BTBR aged mice and control mice. Results indicated there were no significant differences in the number of excitatory synapses, expression of Shank3 protein or shape of dendritic spines in aged BTBR mice and control mice. However, the baseline and evoked glutamate release in aged BTBR mice was lower than control mice. Glutamate is the principal excitatory neurotransmitter in the brain and is important in regulating the balance between neuronal excitation and inhibition. The findings in this study suggest that, unlike in children, ASD in adults is hypoglutamatergic. Thus, there is an age-related glutamate change that occurs in individuals with ASD: excessive glutamate or over activation in the autistic brain at a young age and deficient glutamate or over inhibition in the autistic brain at old age.
Atypical sensory development is found in both human patients and SHANK3 knockout mice. It is known that genes associated with ASD (in this case SHANK3) can shape and affect cerebellum circuit functions, and that changes in the cerebellum affect behavior and cognition. Because of this knowledge, effectiveness of the cerebellum at responding to sensory input and general function of the cerebellum were measured in this study, in addition to the prevalence of ASD symptoms. A method of sensory conditioning was used to study the effect of cerebellar associative sensory learning defects in SHANK3 knockout mice. The SHANK3 knockout mice had delayed or absent responses to stimuli following sensory conditioning, indicating defects in the cerebellum. This suggests that SHANK3, which is typically heavily concentrated in the cerebellum, is partially responsible for regulating sensory learning.
SHANK3 is a gene that assists neurotransmitter connection, synapse formation, and dendrite spine maturation. The autism-associated insertion mutation (InsG) of SHANK3 exon 21 was found in two brothers with clinically identical cases of autism spectrum disorder (ASD), but not in their normally developing brother. This discovery from the University of Texas Southwestern Medical Center suggests that InsG could be a potential cause to certain cases ASD. In a study that recreated InsG in mice, those with the InsG had impaired motor learning and coordination, consistent with the sibling’s symptoms. The group of the InsG mice were then given Tamoxifen while the control group were given a normal diet. The Tamoxifen induced a SHANK3 knock in, causing new segments of SHANK3 to form. As new SHANK3 was synthesized the mice also gained increased motor learning and coordination abilities. The effect of the Tamoxifen on the symptoms of the InsG demonstrated the potential for use as a therapeutic agent.