Unusually high levels of the signaling peptide BDNF, or brain-derived neurotrophic factor, have been detected in blood samples from children with autism. Barbara Hempstead of Weill Medical College at Cornell University and her colleagues propose that BDNF may also be over-expressed in the brains of these children, causing neurological defects that lead to the disorder.
Attentional deficits are a major cause of disability in individuals with autism. Recently, Vikaas Sohal and colleagues described a possible circuit mechanism contributing to attentional deficits in autism[ref]Luongo F.J. et al. Biol. Psychiatry 79, 667-675 (2016) PubMed[/ref]. For the current project, Sohal proposes to identify a specific cellular locus underlying these circuit abnormalities.
A hallmark of autism is impairment in reciprocal social interaction, including inadequate eye contact and failure to recognize emotions. Research shows that the neuropeptide oxytocin modulates social behavior. In mice, rats, monkeys and sheep, for instance, administration of oxytocin enhances social recognition, memory of peers, and development of partner preference and bonding. In people, including those with autism, oxytocin nasal spray can significantly enhance social cognition.
Perturbed neuronal arborization, or branching, and defects in long-range connectivity are likely to be shared mechanisms in many forms of severe autism. Neurotrophic factors (proteins that play a role in the growth and maintenance of neurons) and their cognate receptors, such as brain-derived neurotrophic factor (BDNF) and TrkB, respectively, govern the development of neuronal circuitry, in part, through signaling at the level of intracellular organelles known as endosomes. The protein NHE6 localizes within the cell membranes that form endosomes. Moreover, through its role in mediating the transport of protons (H+) out of endosomes in exchange for the import of sodium (Na+) ions, it contributes to modulating endosome acidity.
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by impairments in social interaction and communication, and restricted, stereotyped behaviors that manifest in early childhood. Research findings have identified widespread changes in the immune system in children with autism.
Dysregulated levels of neuromodulators and other chemical signals may contribute to behavioral characteristics of ASD. Yet previous efforts have often focused on only one signal at a time, and typically provide a static description of signal levels in the brain. In the current project, Mark Andermann and colleagues plan to use novel optical methods to track and control dozens of neuromodulators and peptides in the brain of a genetic mouse model of ASD.
Most individuals with autism experience at least one form of hypersensitivity from the five senses. These alterations in sensory-related behaviors can lead to profound limitations on an individual’s ability to work, interact with family and participate in leisure activities. Furthermore, these atypical responses to otherwise normal sensory stimuli may be closely associated with the core symptoms of autism, such as social deficits and repetitive behaviors. Despite the importance of sensory abnormalities in the pathogenesis of autism, how the brains of individuals with autism receive information from the five senses at the subcortical level and how such information becomes transformed into aversive responses has not been investigated.
The symptoms of fragile X syndrome stem from the loss of a single protein, raising the possibility that reintroducing FMRP could counter the key problems that lead to disrupted signal processing and aberrant behaviors. Turner is proposing a new means to reintroduce a short active fragment of FMRP back into central neurons in the Fmrp1 knockout mouse model to assess its potential utility as a therapeutic strategy to restore circuit and behavioral function in fragile X syndrome.
Seizures are an extreme outcome of excitatory-inhibitory imbalance and are the most common neurological complication in autism spectrum disorder (ASD). Seizures are even more common in syndromic forms of ASD such as Angelman syndrome. In the current project, Ben Philpot’s laboratory aims to identify the circuitry and protein pathways underlying seizures in a mouse model of Angelman syndrome, with the goal of identifying disease-modifying targets to treat seizures. The mechanistic insights yielded by these studies may further guide therapeutically oriented investigations of excitatory-inhibitory imbalance across the broader spectrum of ASDs.
The sensory and neural mechanisms that mediate social communication facilitating attachment and how they are affected in the context of autism spectrum disorder (ASD) are poorly understood. Prairie voles are small rodents that display long-term relationships between peers and mates. Devanand Manoli proposes to understand how specific mutations in two ASD risk genes, Shank3 and Scn2a, disrupt the processing of social cues, leading to the identification of brain regions that could inform targeted interventions to improve social communication in ASD.