Brain Neuropeptide Signaling and Autism Spectrum Disorder
Abstract
Autism spectrum disorder (ASD) is a brain disorder of early childhood onset, characterized by core social interaction impairments and the presence of restricted, repetitive behaviors. ASD is among the most devastating disorders of childhood, affecting 1 in 54 U.S. children. Research over the past few decades has revealed that ASD is highly heritable and, in the majority of cases, polygenically determined (i.e., ASD is frequently caused by multiple “susceptibility genes” acting together). Understanding disease mechanisms in ASD is central to developing effective approaches to its detection and treatment. Although significant progress has been made over the past two decades in identifying ASD “susceptibility genes,” the biological basis of ASD’s behavioral symptoms remains poorly understood. Consequently, there are no laboratory-based diagnostic tests to detect ASD, and there are no commercially available medications that effectively treat ASD’s debilitating core features. To address these challenges, our team has pursued efforts to discover biological markers of ASD in cerebrospinal fluid (CSF), which is more representative of brain biochemistry than blood. We have found that CSF (but not blood) concentrations of the “social” neuropeptide arginine vasopressin (AVP) differentiate ASD cases and controls with high accuracy, and that ASD patients with the lowest CSF AVP concentrations have the greatest clinical symptom severity. Furthermore, we have recently shown that CSF AVP concentration in 0-3-month-old human newborns strongly predicts a medical record diagnosis of ASD later in childhood. Finally, these findings were specific to AVP, as no evidence implicating the nearly structurally identical neuropeptide, oxytocin (OXT), was found. Despite these advances, it is currently unknown whether AVP measured in CSF samples collected from the lumbar region of the back is related to brain AVP production, as AVP is synthesized in the body, in addition to a region of the brain called the hypothalamus. Additionally, AVP itself has not been implicated as a high-confidence ASD “susceptibility gene.” Therefore, we hypothesize that hypothalamic AVP signaling is a “downstream pathway” critical for the expression of ASD symptoms and a point of convergence for multiple ASD “susceptibility genes.” This would explain our past findings linking variation in CSF AVP concentration to clinical symptom severity and why intranasal AVP treatment improves social abilities in ASD patients, as we recently found in a double-blind, randomized, placebo-controlled pilot trial. Indeed, identifying a common biological pathway for the development of ASD has important implications for improving diagnosis across the life span, as well as for better understanding mechanisms of heterogeneous clinical expression in the context of social symptom severity, in alignment with two core Department of Defense ARP Idea Development Award Areas of Interest. This project will be conducted by a team of basic scientists and clinicians using an archive of post-mortem brain tissue, CSF samples, and blood samples that were collected from each individual at the same time. In this project, we will study 20 people with ASD and 20 controls. This project will bring together multiple lines of compelling evidence and state-of-the art tools to test whether hypothalamic AVP cell number and hypothalamic AVP gene expression are diminished in individuals with ASD vs. controls, whether CSF AVP concentration is a valid surrogate of hypothalamic AVP production, and whether these biological measures are related to clinical symptom severity. We will also use gene expression profiling and advanced statistical methods to identify genes involved in regulating hypothalamic AVP production. Tremendous strides have been made over the past two decades in identifying ASD “susceptibility genes.” Although we now know that the vast majority of “genetic burden” in ASD is complex and polygenic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110210
Entities
People
- Karen J. Parker
Organizations
- Stanford University
- United States Army