Abstract not available.

Autism spectrum disorder (ASD) is a complex disorder with large individual variability, where every case has differences in the type and severity of symptoms. Despite the recent increase in diagnoses, scientists have advanced considerably less in their understanding of the mechanisms of ASD because few individual genes that are implicated in ASD are mutated in much more than 1% of patients. One proposed mechanism is that the dysfunction of GABAergic interneurons may play a role in the development and progression of the disorder by interrupting the excitatory and inhibitory balance of neural networks. In our research, we elucidate the role of one class of interneurons in ASD by knocking out a high-risk gene (phosphatase and tensin homologue on chromosome ten, or PTEN) selectively in somatostatinexpressing (SOM+) interneurons. Since many symptoms of autism spectrum disorder present themselves as social anxieties, we test our mouse model in a variety of settings to observe social interaction and social preference, anxiety-like behavior, and repetitive stereotyped behavior. We found that in the SOM+ conditional knockout of PTEN, mice had elevated levels of anxiety and fear recall, suggesting a potential disruption of amygdala function. We then investigated potential dysfunction at the cellular and circuit levels using confocal microscopy, electrophysiology, and 2P local circuit mapping. We found that SOM+ cells lacking PTEN were overgrown morphologically, with larger cell bodies and larger, more complex dendritic arbors. Additionally, SOM+ cells in the central amygdala (CeA) lacking PTEN had elevated levels of excitatory drive from the basolateral amygdala (BLA) as well as a drastic disruption of lateral inhibition within the CeA, seen by decreased connection probability and reduced inhibitory post synaptic currents. Given what is known about central amygdala circuitry, these deficits in CeA SOM+ neuron activity conceivably underlie the fear and anxiety-related phenotype observed in mice with a conditional SOM+ PTEN knockout. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection

The media has the ability to influence societal perceptions about important issues. This study involved a dual examination of content and effects of news media representations of a prominent health issue—autism spectrum disorder (ASD) that now affects 1 in 88 individuals (CDC, 2013). Study 1 examined the presence of attributions of ASD and signaling “stigma” cues in news media and Study 2 investigated the effects of attributions of ASD emphasized in news media on community members’ emotions, behavioral intentions, and behaviors toward the disability. Study 1 revealed associations between certain attributions and signaling “stigma” cues and indicated news circulation plays a role in the appearance of cause attributions and social skill deficit cues. The results also illuminated intriguing trends in the presence of certain attributions of ASD and signaling “stigma” cues in news media over the past 16 years. Study 2 shed light on the direct and indirect effects of attributions about ASD emphasized in news stories on community members’ emotions, behavioral intentions, and actual behaviors; these findings partially align with attribution theory. This research provides a holistic understanding about the presence and power of language emphasized in news stories about ASD. Implications and directions for future research are discussed.

Parent knowledge of ASD may be relevant to early identification and intervention services for children with ASD. By understanding how knowledgeable parents of young children are about ASD, researchers and practitioners can intervene and educate this population. This study sought to determine the knowledge base of ASD among parents with children five years and younger and if developmental, behavioral, and autism-related concerns predict knowledge of ASD. The sample of parents consisted of 167 mothers and fathers. All participants completed a knowledge questionnaire (i.e., ASKSG) and reported their level of developmental, behavioral, and autism-related concerns of their oldest child between the ages of 2 and five years. Results revealed that the sample of parents had a relatively low knowledge base of ASD, as determined by a percentage correct on the ASKSG of 43.9% (SD=20.1). Additionally, developmental, behavioral, and autism-related concerns did not collectively predict the sample’s knowledge of ASD; however, autism-related concerns independently predicted knowledge. The results of this study provide information to researchers and practitioners that can be used to educate parents of young children regarding ASD. By doing so, early and appropriate identification of ASD may be improved. In turn, children and families may have increased access to early intervention services and thus may result in better developmental outcomes.

<p>  </p> <p>Recent advancements in genetics have revealed that <em>SCN2A</em> is one of the leading genes associated with neurodevelopmental disorders including autism spectrum disorder and epilepsy. In particular, loss-of-function and truncation variants account for a majority of cases. As there are no current treatments specific for <em>SCN2A</em>, the neuropharmacogenomics field has strived to further elucidate the role of <em>SCN2A</em> in neurodevelopment to identify intervention targets. Rodent models offer <em>in vivo</em>, pre-clinical insight into the effects of genetic variation on behavior, biochemistry, and electrophysiology as well as the mechanisms on molecular, cellular, and circuitry levels. Due to <em>SCN2A</em>’s critical involvement in the initiation and propagation of action potential neuronal firing early in neurological development, full null homozygous knockout of <em>Scn2a</em> in mice is perinatal lethal. Furthermore, canonical heterozygous knockout of <em>Scn2a </em>in mice does not render phenotypes that recapitulate <em>SCN2A</em> deficiency in humans. Therefore my dissertation aims at developing a mouse model that better parallels the human condition, then using that pre-clinical platform to explore precision medicine.</p> <p>  </p> <p>Using the unconventional strategy of gene trapping, we generated mice with a severe reduction in <em>Scn2a</em> expression, resulting in significant behavioral and electrophysiological differences from neurotypical wild-type mice with full <em>Scn2a</em> expression, but enough residual expression that the <em>Scn2a</em>-deficient mice survived into adulthood. The severely decreased sociability accompanied by increased high and low order repetitive behaviors observed with the <em>Scn2a</em>-deficient mice suggest autism-like phenotypes. In addition, <em>Scn2a</em>-deficient mice also displayed other co-morbidities of neurodevelopmental disorders including atypical innate behavior, increased anxiety, increased sensitivity to stimuli, motor discoordination, and impaired learning and memory. On the electrophysiological level, these mice displayed enhanced intrinsic excitabilities of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in seizures and social behavior. This increased excitability was autonomous and reversible by the genetic restoration of <em>Scn2a</em> expression in adult mice. Further, RNA-sequencing revealed a downregulation of multiple potassium channels as well as differential expression of glutamate excitatory and GABA inhibitory signaling, which led to the pursuit of targeting these pathways. Indeed, the use of potassium channel openers alleviated the hyperexcitability of <em>Scn2a</em>-deficient neurons, thus supporting the pursuit of these targets.  </p> <p>Since characterization of the <em>Scn2a</em>-deficient mouse model revealed disruption in excitatory and inhibitory pathways, excitatory/inhibitory balance was examined further as a precision medicine target. Increasing <em>Scn2a</em> expression throughout the whole brain by excising the gene trap, as well as specific targeting of the striatum and the neurons that project to it using a retrograde viral vector, rescued social deficits. However the striatum-specific injection did not lead to a social rescue. This shifted the focus to the neurons that project to the striatum such as the medial prefrontal cortex. Using chemogenetics to reduce excitatory signaling in the prelimbic region of the medial prefrontal cortex, we were able to increase the social behavior in <em>Scn2a</em>-deficient mice. Synthesizing the results from the retrograde striatum and prelimbic-specific rescue, the next hypothesis tested was a circuity-level manipulation of the medial prefrontal cortex projections to the striatum. Retrograde control (striatum) of chemogenetics (medial prefrontal cortex) decreased the excitatory signaling in the medial prefrontal cortex neurons that project to the striatum, which also led to improved sociability. On the other side of the excitatory/inhibitory balance, increasing inhibitory signaling through acute exposure to small-molecule GABA receptor positive allosteric modulators, clonazepam and AZD7325, rescued sociability.</p> <p>This dissertation opens up new avenues of research by supporting the use of a pre-clinical mouse model of <em>Scn2a</em> deficiency to advance the study of underlying mechanisms behind <em>SCN2A</em>-related neurodevelopmental disorders. Although the results of this dissertation need additional validation such as cellular support, the data and results in this dissertation can serve as a guide to further explore excitatory/inhibitory balance as a neuropharmacogenomics precision medicine target to treat <em>SCN2A</em>-related neurodevelopmental disorders. </p> <p><br></p> <p><br></p>

Autism spectrum disorders (ASD) are characterised by impairments in social interaction and communication, and repetitive and compulsive behaviours. The heterogeneous nature of ASD is underpinned by complex genetic networks; hence there is no known single genetic cause of ASD. It is therefore imperative to identify both genetic and epigenetic loci associated with ASD or specifically ASD endophenotypes. This may aid in earlier interventions for ASD if molecular biomarkers were identified. The serotonergic system has a longstanding association with ASD, and the differential expression of the serotonin transporter gene (SLC6A4) is linked to particular ASD traits. This study focuses on a length polymorphic repeat region (5-HTTLPR) upstream of the SLC6A4 promoter, and SLC6A4 promoter DNA methylation. The short variant of 5-HTTLPR is directly linked to lowered SLC6A4 expression and is at higher frequencies in ASD populations. DNA methylation at the promoter of SLC6A4 is also known to affect SLC6A4 expression. This study hypothesis is that there is differential regulation of SLC6A4, through changes in 5-HTTLPR and DNA methylation, between an ASD and control cohort. This differential regulation was also predicted to differ between ASD endophenotypes based on severity levels categorised by ADOS-2 (Autism Diagnostic Observation Schedule-2). ASD children (n=50) were compared to an agematched control group (n=13), all of whom were characterised phenotypically by an ADOS-2 assessment. The 5-HTTLPR and SLC6A4 promoter DNA methylation were analysed using restriction fragment length polymorphic analysis and the EpiTYPER assay, respectively. Significant differences were found in SLC6A4 regulation between the ASD and control group. A significant increase in frequency of individuals homozygous for the 5-HTTLPR long variant in the control group was observed when compared to the ASD cohort (p=0.049); with the long allele conferring reduced risk of ASD. Overall DNA methylation at the SLC6A4 promoter region was significantly decreased in the ASD cohort (p=0.011), the moderate ASD endophenotype (p=0.004), language impaired endophenotype (p=0.003), as well as the more severe socially and repetitive and restricted behaviour groups (p=0.006 and 0.045, respectively), when compared to the control cohort. Reduced levels of DNA methylation at CpG 30 in the target region were found to be significantly associated with higher levels of repetitive behaviour (p=0.001). The data from this study implicates the involvement of the serotonin transporter in overall ASD aetiology, specifically within the language impaired and repetitive and restricted behaviour endophenotypes. The data highlight the importance of maintaining appropriate methylation levels in order to modulate SLC6A4 expression. The regulatory mechanisms that control DNA methylation at the SLC6A4 promoter are unknown and need to be identified to completely understand how dysfunction of the serotonergic system is involved in ASD.

Individuals with autism spectrum disorder (ASD) display deficits in communication and social interaction that can impact their ability to function in daily environments. To remediate these deficits, it is critical for professionals to use effective interventions. While there are many evidence-based practices (EBPs) identified for ASD (e.g., video modeling), the adoption of these EBPs may not occur automatically. Existing research suggests professionals have a generally favorable impression of video modeling. However, little research has examined opinions and applied use of video modeling, which was the purpose of the present study. Using survey methodology, data were collected from 510 professionals in various disciplines (e.g., special educators, speech-language pathologists [SLPs], and behavior analysts [BCBAs]). Data were analyzed primarily via factor analysis and multiple regression. Factor analysis was used to examine the underlying structure of the instrument, revealing two predominant factors: (1) interest in and (2) perceived accessibility of video modeling. Multiple regression was used to examine which demographic characteristics (e.g., age and years of experience) were associated with each factor. Results indicated that BCBAs and SLPs perceived video modeling as more accessible. In terms of interest, professionals who worked with preschool-aged students, who worked in a suburban location, and who had an extended family member with ASD showed higher interest in video modeling. Implications for practice and future research are discussed.

Due to the nature of the complexity of the diagnosis of autism spectrum disorder (ASD), elementary-aged students with this disorder require a holistic, team-based approach to education in the school setting. A review of current literature has found that while interprofessional collaborative practice (ICP) in the school setting is effective and often recommended for students with ASD, a variety of barriers have resulted in fragmented care. Additionally, there is limited research supporting a cohesive model of interprofessional collaborative practive when working with students with ASD in the elementary school setting. This problem is likely leading to decreased outcomes for elementary-aged students with ASD. Occupational therapy practitioners’ role as holistic, client-centered practitioners creates an ability to bridge the gaps between the often-fragmented goals of the members of an interprofessional team. Interprofessional collaboration in the school setting between occupational therapy practitioners, physical therapy practitioners, psychologists, speech and language pathologists, social workers, and teachers is crucial to addressing the multi-faceted needs of children with ASD and providing the highest level of service in accordance with the Occupational Therapy Practice Framework: Domain and Process, Fourth Edition. This doctoral project aims to add to the limited body of research in this area in order to fulfill this role. The TOPPSS Model of Interprofessional Collaboration is an evidence-based school-year long plan of structured collaboration between staff members working with students with ASD in an elementary school setting through a professional development workshop. The workshop will educate participants on the TOPPSS Model of Interprofessional Collaboration. The participants that are being targeted for this workshop include elementary school-based teachers (T), occupational therapy practitioners (O), physical therapy practitioners (P), psychologists (P), speech-language pathologists (S), and social workers (S). The overall aim of this program is to improve interprofessional collaborative practice (ICP) among the participants in order to increase positive outcomes for students with ASD.

Thesis advisor: Stefano Anzellotti / Autism Spectrum Disorder (ASD) displays uniquely in every individual, creating disparities in symptom severity, genetics, and functional connectivity. Examining the relationship between genetic and functional connectivity variability could help to better understand individual differences in ASD. From this, improved diagnosis, treatment, and understanding of ASD can be developed. To resolve individual differences in symptom severity and presentation, I generated matrices of subject functional connectivity data and compared this to gene expression maps. Multivariate regression analysis was performed on the data to anticipate ASD symptoms from these correlation matrices and to establish which genes have the largest impact on these predictions. The ANOVAs ran on the data were not significant, but there were several genes implicated in specific aspects of ASD. STX1A, MVP, CDKL5, and RABEP2 were the only genes correlated across more than one subtype of ASD. These results pave the way for future research to investigate the roles of these genes in a larger size of ASD subjects. / Thesis (BS) — Boston College, 2023. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: Psychology and Neuroscience.

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