Regulation and Function of Activity-Dependent Homer in Synaptic Plasticity

Abstract

Alterations in synaptic signaling and plasticity occur during the refinement of neural circuits over the course of development and the adult processes of learning and memory. Synaptic plasticity requires the rearrangement of protein complexes in the postsynaptic density (PSD), trafficking of receptors and ion channels and the synthesis of new proteins. Activity-induced short Homer proteins, Homer1a and Ania-3, are recruited to active excitatory synapses, where they act as dominant negative regulators of constitutively expressed, longer Homer isoforms. The expression of Homer1a and Ania-3 initiates critical processes of PSD remodeling, the modulation of glutamate receptor-mediated functions, and the regulation of calcium signaling. Together, available data support the view that Homer1a and Ania-3 are responsible for the selective, transient destabilization of postsynaptic signaling complexes to facilitate plasticity of the excitatory synapse. The interruption of activity-dependent Homer proteins disrupts disease-relevant processes and leads to memory impairments, reflecting their likely contribution to neurological disorders.

Synaptic activity and strength are reflected by changes in the post-synaptic secretory pathway

“…whether the features of a synapse influence the local distribution and abundance of the elements of the secretory pathway, or their proximity to the synapse, we designed a high throughput experiment that enabled simultaneous super-resolution imaging of multiple proteins and parameters in cultured hippocampal neurons. The parameters selected to define synapses were the fluorescence signal intensities of the following: homer, a postsynaptic structural marker 44 ; vGLUT1, a marker of the entire pre-synaptic vesicle population of excitatory nerve terminals in these cultures 46 ; and live labelling of SYT1 for identifying only the actively recycling synaptic vesicles in pre-synaptic boutons 48 . While the first two markers provide indications on the strength of the synapse, the latter is a proxy for synaptic activity (Fig.…”

“…The amplitude of the post-synaptic response, commonly referred to as the synaptic strength, can be modulated by changes at both the pre-and post-synaptic levels (for reviews see [37][38][39][40][41][42] ). At the post-synapse, larger post-synaptic densities (PSD) reflect a higher number of functional receptors, and hence a stronger and more potentiated synapse 43,44 . At the pre-synaptic level, synaptic strength can be modulated, among others, by the availability of vesicles and release machinery proteins 45 .…”

Transcriptional corepressor SIN3A regulates hippocampal synaptic plasticity via Homer1/mGluR5 signaling

“…The Group I mGluRs play roles in both synaptic potentiation and depression, via agonist-dependent and -independent signaling, and it has been shown that enhancing mGluR5 activation with positive allosteric modulators enhances LTP (48). Long-and short-isoform Homer1 interact with an intracellular domain of mGluR1/5 and differentially modulate signaling through downstream effectors (52). CDK5 phosphorylates the Homer1-binding domain of mGluR5, increasing its affinity for HOMER1 and altering its trafficking and association within the PSD (28).…”

Distinct and Overlapping Expression Patterns of the Homer Family of Scaffolding Proteins and Their Encoding Genes in Developing Murine Cephalic Tissues

“…Among the short Homer proteins, only the short Homer1 splice isoforms, namely Homer1a and Ania-3, have been characterized in terms of expression and function [7,78,79]. Unlike the long Homer isoforms, which are constitutively expressed in both neuronal and non-neuronal tissues [3,6,7,[28][29][30][31][32][33]78,79], Homer1a and Ania-3 have been shown to be neuron-specific splice isoforms [1,2,78] and to be rapidly and transiently upregulated upon neuronal stimulation [1][2][3]6,78,79]. We found that at E14.5, in addition to other brain regions, the hippocampal formation was enriched with Homer1 mRNA and protein.…”