Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

Abstract

Understanding the mechanisms underlying autism spectrum disorders (ASD) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops, and provide detailed commentary for exemplar genes within each module.

Molecular and Neural Functions of Rai1 , the Causal Gene for Smith-Magenis Syndrome

“…Designing treatment strategies for neurodevelopmental disorders associated with genetic mutations requires a comprehensive understanding of their genetic causes, molecular functions of the affected genes, and the cell types that underlie different symptoms (Kaiser and Feng, 2015; Mullins et al, 2016; Wells et al, 2016; Zoghbi and Bear, 2012). In this study, we present an extensive functional analysis of Rai1 —a causal gene for two syndromic neurodevelopmental disorders (SMS and PTLS)—at molecular and behavioral levels.…”

Neuropilin-2/PlexinA3 Receptors Associate with GluA1 and Mediate Sema3F-Dependent Homeostatic Scaling in Cortical Neurons

“…These observations, in combination with current thinking regarding the relationship between homeostatic plasticity and epilepsy (Swann and Rho, 2014), shed light on how Sema3F-Npn-2 signaling may contribute to maintaining the balance between excitation and inhibition to control overall network homeostasis. Local scaling interactions may also be regulated by Sema3F following the activation of individual synapses and subsequent weakening of neighboring ones (Mullins et al, 2016). Secreted semaphorin-mediated regulation of homeostatic scaling at mature synapses provides examples of how signaling cascades critical for neural development also impact adult neural plasticity, encouraging further exploration into the degree to which neural developmental mechanisms underlie adult synapse function in health and disease.…”

ASD Validity

“…By contrast, Khan et al (2015) proposed that ASD resulted from underconnectivity in local brain regions when activated by a Bfunctionally relevant task^(p. 1407). Mullins et al (2016) posited that mutations in the FMR1 gene and TSC genes disrupt long-term depression (LTD) and long-term potentiation (LTP), and therefore, these mutations in ASD cause atypical LTP and LTD processes that impair the excitation-inhibition balance in brain development and function which determines ASD (Mullins et al 2016). Robertson et al (2015) claimed that the Bprime suspectŝ ingle cause for ASD was disrupted GABAergic signaling that impaired neurodevelopment and cortical computations.…”