ASD Case Study

Associated with autism, there are a number of conditions comorbid to ASC. There is a high prevalence of epilepsy in individuals with autism, with a 1 in 4 prevalence, with seizures often starting in early childhood or adolescence. Tourette’s syndrome also has a higher prevalence within ASC then the neuro-typical population, with a prevalence of 6.5% compared to 2-3%. This may be due to abnormalities in dopamine, glutamate and serotonin abnormalities in autism. There is also a high proportion of individuals with learning difficulties, whether mild, moderate or severe, with a reporting from as low as 20% up to 70% prevalence.

ASD is a pervasive developmental disorder that consists of abnormal development and functioning of the brain. ASD may involve deficits in social behaviors, abnormalities in communication, cognitive delays, and repetitive behaviors (UC San Diego Autism Center of Excellence, 2016). ASD is a broad spectrum neurological disorder with a variety of symptoms affecting each individual differently (Debbaudt & Rothman, 2001). ASD involves severe impairments of reciprocal social interactions, impaired

Reduction in brain and neuronal sizes with an increase in cell density is consistently observed in several brain regions of patients with RTT (Calfa et al, 2015). These areas include the cerebral cortex, hypothalamus and the hippocampal formation (Belichenko et al, 2009). According to Belichenko (2009) dendritic morphology of neurons has been observed in a number of neurodevelopmental disorders, including RTT. An autoradiography done in the frontal cortex and basal ganglia of individuals affected by RTT have shown complex abnormalities in the density of glutamate receptors such as NMDA-(N-methyl-d-aspartate), AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), kainate- and metabotropic receptors (Blue et al, 1999).The prefrontal cortex of girls who were 2-8-year-old had increased NMDA receptors as compared to 10 year old girls who had reduced NMDA receptors. Receptor density was dependent on age of the patient (Blue et al, 1999). Changes in the neurons, such as decreased dendrites and decreased dendritic spine numbers are observed; particularly, changes in the hippocampal CA1 pyramidal neurons are shown (Chapeau et al, 2012). When compared to an age-matched control, researchers noticed that RTT affected patients had lower dendritic spine density in their

ASD is rather an umbrella terminology, used to describe varying behaviours, which affect the way some groups of people process and act in response to their surrounding stimuli (FP; 2012). As a ‘spectrum’ of disorders, this includes autism, Asperger’s syndrome

Mutations that occur during transcription are also linked to the expression of genes associated with Autism Spectrum Disorder. ASD candidate genes are genes normally related to synapse function, but when the enzyme topoisomerase is inhibited, the genes are not fully expressed4, factoring into the phenotypic expression of Autism. The individuals studied who were affected by ASD had a numerous amount of mutated genes relating to transcription function4. This result illustrates the relationship between transcription and the phenotypic expression of autism.

Neurological disorders such as Alzheimer’s disease, autism spectrum disorders (ASD), and schizophrenia impact behavior and cognitive processes. While the symptoms for these diseases vary, they share disruptions in synapse development and spine formation. In the mammalian nervous system, dendritic spines are small, dynamic protrusions on neurons that develop in response to increased presynaptic activity. Although spine dynamics throughout development have been well studied, very little is known about the genes involved in spine formation. A recent study in our laboratory discovered spiny projections on a group of inhibitory neurons called DD neurons in C. elegans. Using C. elegans as a model system, the goal of this project is to identify genes responsible for dendritic spine formation. Specifically, I will 1) conduct a forward genetic screen and examine candidate axon guidance molecules to identify genes involved in dendritic spine formation, and 2) examine the effect hyper- and hypo-presynaptic activity has on the development of spines using locomotory changes, such as thrashing and microfluidic assays, and cell-specific changes using channel rhodopsin and temperature sensitive alleles. Given the strong homology between C. elegans and mammalian genes, this research will help identify conserved mechanisms underlying spine formation and maintenance. Ultimately, understanding spine development will help shape the treatment and prevention of

Ketone bodies appear to have a conceivable neuroprotective role in NDD by decreasing oxidative stress through reducing ATP production via indirect inhibition, changing mitochondrial energy metabolism by altering cellular communication, increasing antioxidant activity and reducing neuronal death (Gano, Patel, Rho 2014). Interest in investigating the probable connection between ketone bodies produced via KD and oxidative stress and mitochondrial dysfunction is on the rise. Next, a review of three current original studies exploring ketone bodies effect on the progression of several of the most notable NDD’s: AD, PD, and ALS, respectively.

The disease functions by causing neurons to degenerate and lose their synapses with other nerves, thus cutting down severely on the intercellular communication which lies at the heart of all behavior. (1).

Sahar Salimi-Mosavi, Human Biology Program, University of Toronto, Dr. Lili-Naz Hazrati, Department of Laboratory of Medicine and Pathology, Tanz Centre for Research in Neurodegenerative Diseases

Neurogenetics Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

Consequently, the disorder is characterised by many behavioural, anatomical and neurochemical abnormalities (Bencherif, Stachowiak, Kucinski & Lippiello, 2012). The behavioural states

Autosomal dominant mutations in APP, PSEN1, or PSEN2 that alter APP processing and the production or self aggregation of Aβ, promote aggregation and accumulation of Aβ in brain causing early-onset AD (Bertram et al., 2010).

It has been known that PD is a disorder affecting the basal ganglia. The term basal ganglia is generally applied to a collection of nuclei situated deep within the cerebral hemispheres, lying laterally to the thalamus (Gazzeniga, George, and Mangun, 2008). The basal ganglia are important subcortical structures. They are composed of five nuclei: caudate, putamen, globus pallidus, subthalamic nucleus, and substantia nigra. These nuclei are not thought of a single anatomical entity; rather, they form a functional unity whose contribution is greatly to motor control. Interestingly, this system does not influence movement through spinal cord pathways, but rather acts as part of a feedback loop to all areas of the cerebral cortex, with primary input into motor areas (Aird, 2000). A number of excitatory and inhibitory neurotransmitters are what control this whole process, and a balance of both is required to ensure that smooth, purposeful movement takes place. In order to understand the pathways of which the basal ganglia take part in, it is essential to know the input and output connections of the basal ganglia. The input

There is a critical need to design a novel strategy targeting ASD risk genes involved in the Wnt pathway. The major gap in current knowledge that we will address in this proposal is to determine how PV neuron- specific CTNNB1 KO affects animal behaviors and to what extent Wnt agonists reverse the behavioral deficits. We expect to identify the defect that is involved in PV neurons specific to CTNNB1 knockout mice. Moreover, we have identified several bioactive compounds with diverse mechanisms of action that can potentiate the Wnt pathway in human NPCs, including approved drugs and probes suitable for in vivo use31, 32. Repurposing these drugs for ASD will be exciting because they act through different mechanisms than current experimental therapies now. Our cKO mice provide an ideal animal model to examine the extent to which targeting Wnt pathway can ameliorate the behavioral deficits. If small molecules targeting Wnt pathway in this study can alleviate behavioral deficits, a whole new "druggable" pathway will further identify more active molecules/drugs that can be directly applied to the ASD patients. This contribution will be significant because it is an important step to allow modulation of the Wnt signaling pathway at interneurons and may lead to development of a pharmacologic approach to correct ASD-related behavioral defects, thereby improving the lives of ASD patients. What is learned in this study will be applicable to other ASDs caused by mutations associated with

The neurobiology of AD is well understood now and the search for better treatment options is still on. This provides an opportunity for more research on integrated approach using existing therapies, traditional and alternative medicines with newer treatments and potential candidates for management of AD.