Activity-dependent modulation of neural circuit synaptic connectivity

Abstract

In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; (1) early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and (2) subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circuits are “hard-wired” in a purely activity-independent manner. This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution. These recent studies reveal that activity-dependent mechanisms are indeed required to refine circuit maps in Drosophila during precise, restricted windows of late-phase development. Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS) and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function. This review focuses on our current understanding of activity-dependent synaptic connectivity in Drosophila, primarily through analyzing the role of the fragile X mental retardation protein (FMRP) in the Drosophila FXS disease model. The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail.

The nonsense-mediated decay pathway maintains synapse architecture and synaptic vesicle cycle efficacy

“…This requirement has been characterized for a number of mRNA-binding proteins, prominently including the fragile-X mental retardation protein (FMRP) (Gatto and Broadie, 2008;Pan and Broadie, 2007; Pan et al, 2008;Tessier and Broadie, 2008;Tessier and Broadie, 2009). Here, we show that loss of mRNA regulation via disruption of the NMD pathway also impairs synaptic architecture at the well-characterized Drosophila NMJ.…”

“…Together, our studies indicate that NMD activity is required in at least two disparate synaptic classes, retinal photoreceptor synapses and neuromuscular junction, suggesting that an NMD-mediated protective mechanism is broadly important in synapses throughout the nervous system. We, and others, have exerted a great deal of effort exploring the roles of mRNA regulation in synaptic mechanisms (Antar and Bassell, 2003;Gatto and Broadie, 2009;Pfeiffer and Huber, 2009;Tessier and Broadie, 2009;Yan et al, 2009). In particular, mechanisms of mRNA stabilization, trafficking, RISC-mediated degradation and localized translation have all been recently determined to occur in proximity to synapses and/or with important roles in synapse regulation (Giorgi et al, 2007;Hengst and Jaffrey, 2007;Lin and Holt, 2007;Sebeo et al, 2009;Yan et al, 2009).…”

Drosophila DFMR1 Interacts with Genes of the Lgl-Pathway in the Brain Synaptic Architecture

“…It regulates the composition of the postsynaptic glutamate receptor subunits (7). A model was proposed, suggesting that dFMRP stabilizes dlg1-mRNA and its protein level (52). In the light of this model, our immuno-staining results get one possible explanation.…”

The cell polarity scaffold lethal giant larvae regulates synapse morphology and function

“…LGL and FMRP (Zarnescu et al, 2005), an RNA-binding translational regulator of activity-dependent changes in synaptic structure/function (Tessier and Broadie, 2009);2) LGL and DLG, likewise a tumor suppressor and cell-polarity scaffold (Ohshiro et al, 2000) with critical roles controlling synaptic architecture/ function (Mathew et al, 2002;Zhang et al, 2007a;Wang et al, 2011b);and 3) LGL and the Wnt/Wg signaling pathway, also a key regulator of cell polarity and synaptic structure/function (Dollar et al, 2005;Miech et al, 2008;Korkut et al, 2009). Although many of these interactions remain to be explored in the synaptic context, this study provides enticing evidence that LGL may link synaptic translational regulation and the directional localization of encoded proteins to signaling complexes on both sides of the synaptic cleft.…”