Impaired activity-dependent neural circuit assembly and refinement in autism spectrum disorder genetic models

Abstract

Early-use activity during circuit-specific critical periods refines brain circuitry by the coupled processes of eliminating inappropriate synapses and strengthening maintained synapses. We theorize these activity-dependent (A-D) developmental processes are specifically impaired in autism spectrum disorders (ASDs). ASD genetic models in both mouse and Drosophila have pioneered our insights into normal A-D neural circuit assembly and consolidation, and how these developmental mechanisms go awry in specific genetic conditions. The monogenic fragile X syndrome (FXS), a common cause of heritable ASD and intellectual disability, has been particularly well linked to defects in A-D critical period processes. The fragile X mental retardation protein (FMRP) is positively activity-regulated in expression and function, in turn regulates excitability and activity in a negative feedback loop, and appears to be required for the A-D remodeling of synaptic connectivity during early-use critical periods. The Drosophila FXS model has been shown to functionally conserve the roles of human FMRP in synaptogenesis, and has been centrally important in generating our current mechanistic understanding of the FXS disease state. Recent advances in Drosophila optogenetics, transgenic calcium reporters, highly-targeted transgenic drivers for individually-identified neurons, and a vastly improved connectome of the brain are now being combined to provide unparalleled opportunities to both manipulate and monitor A-D processes during critical period brain development in defined neural circuits. The field is now poised to exploit this new Drosophila transgenic toolbox for the systematic dissection of A-D mechanisms in normal versus ASD brain development, particularly utilizing the well-established Drosophila FXS disease model.

Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory

“…FMRP is required for activity-dependent changes in MVP2 dendritic arborization Activity-dependent changes in synaptic connectivity are hypothesized to underlie the dysmorphic dendrites characterizing FXS (Doll and Broadie, 2014). We therefore tested target MB-ENs for manifestation of activity-dependent restructuring of dendritic arbors during the 24-h critical period immediately following eclosion Broadie, 2008, 2012).…”

“…Activity-dependent remodeling of neural connectivity is a hallmark of late critical period brain development (Doll and Broadie, 2014). Following early overproduction, synapses undergo activitydependent pruning to achieve the mature architecture, optimizing circuit function and behavioral output (Katz and Shatz, 1996;West and Greenberg, 2011).…”

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

“…Similar to the mouse FXS model (Bilousova et al, 2009;Sidhu et al, 2014), the Drosophila FXS disease model exhibits Mmp dysfunction as an underlying cause of neurodevelopmental phenotypes (Siller and Broadie, 2012). Neural defects in the Drosophila FXS model, including impairments in both morphological and functional synaptic differentiation (Doll and Broadie, 2014) are remediated by pharmacological or genetic Mmp inhibition (Siller and Broadie, 2011).…”

Temporal course of gene expression during motor memory formation in primary motor cortex of rats

“…accumulation vs. reduction of certain proteins (Bagni, Tassone, Neri, and Hagerman, 2012). The absence of FRMP impairs axon growth and guidance (Doll and Broadie, 2014) and formation of dendritic spines (Penzes, Cahill, Jones, VanLeeuwen, and Woolfrey, 2011).…”