Biology subjects

Trotter, J. H.

Publications and source records attributed to Trotter, J. H..

4 recordsLinked to original sources

bioRxiv2026

ESCRT-0 regulates AMPA receptor currents and Ca2+- dependent signaling

Membrane protein trafficking is essential for synaptic growth, maintenance, function, and plasticity, and involves the regulated exocytosis and endocytosis of proteins to and from the pre-and post-synaptic membranes. Defects in the clearance of membrane proteins can lead to the accumulation of ubiquitinated membrane proteins and contribute to neurodegenerative disease. The ESCRT (endosomal sorting complexes required for transport) machinery binds and sorts ubiquitinated membrane proteins into lysosomes for degradation, yet the presence and function of ESCRTs in sorting ubiquitinated AMPA and other receptors at the post-synapse remain unclear. Here we show that the ubiquitin-binding ESCRT-0 protein, Hrs, localizes to both pre- and post-synapses, and levels are modulated by neuronal activity, increasing and decreasing with higher and lower neuronal activity, respectively. Phosphoproteomic profiling of Hrs-depleted post-synaptic membranes revealed a role for Hrs in glutamatergic synaptic transmission, including long-term potentiation. In addition, Hrs-depleted neurons showed faster AMPAR current kinetics and reduced amplitude in whole-cell patch-clamp recordings. Genetic deletion of neuronal Hgs in mice led to reductions in phosphorylated CaMKII- and -{beta} (T286/T287) and structural proteins, PSD-95 and gephyrin, suggestive of LTD (long-term depression)-like synaptic depression. In contrast, Hrs overexpression led to increases in Ca2+-dependent signaling, including protein kinase C (PKC) and PKC substrate, AMPAR subunit GluA1-S831, a site which increases conductance. Together, these findings identify a dynamic, bidirectional role for Hrs at the post-synapse as it both senses and is modulated by neuronal activity, ultimately impacting excitatory synaptic strength. Significance StatementSynaptic plasticity relies on dynamic trafficking and turnover of membrane proteins, including AMPA-type glutamate receptors (AMPARs), yet how receptor trafficking intersects with ubiquitin-mediated sorting pathways at synapses remains unclear. We show that the ubiquitin-binding ESCRT-0 protein, Hrs, localizes to both pre- and post-synapses, and its abundance is bidirectionally regulated by neuronal activity. Genetic depletion of Hrs in mice reduces CaMKII phosphorylation and impacts AMPAR channel surface localization. In contrast, neuronal-specific Hrs overexpression led to enhanced GluA1 and protein kinase C substrate phosphorylation, suggesting altered AMPAR trafficking, subunit composition, and/or function. Thus, Hrs emerges as a modulator of glutamatergic signaling, coupling ubiquitin-mediated receptor sorting to the fine-tuning of synaptic transmission, with direct implications for learning and memory in health and disease.

neuroscience↗

bioRxiv2022

A combinatorial code of neurexin-3 alternative splicing controls inhibitory synapses via a trans-synaptic dystroglycan signaling loop

Disrupted synaptic inhibition is implicated in most psychiatric disorders, yet the molecular mechanisms that shape and sustain inhibitory synapses are poorly understood. Here, we find that the function of a subset of inhibitory synapses in brain is controlled by binding of presynaptic Neurexin-3 to postsynaptic dystroglycan, adhesion molecules that are associated with cognitive impairments. We found that Neurexin-3 alternative splicing at two sites, SS2 and SS4, acts as an and/or logic gate to regulate the release probability, but not the number, of inhibitory synapses in olfactory bulb and prefrontal cortex. The same SS2 and SS4 splice variants that enable inhibitory synapse function also allow binding of Neurexin-3 to dystroglycan. Inactivation of postsynaptic dystroglycan, in turn, produces a similar decrease in release probability as the presynaptic Neurexin-3 deletion. Furthermore, a minimal dystroglycan-binding construct of Neurexin-3 fully sustains inhibitory synaptic function, suggesting that trans-synaptic dystroglycan binding is not only necessary but also sufficient for inhibitory synapse function. Thus, Neurexin-3 enables a normal release probability at inhibitory synapses via a trans-synaptic feedback loop requiring binding of presynaptic Neurexin-3 to postsynaptic dystroglycan.

neuroscience↗

bioRxiv2021

The Molecular Logic Organizing the Functional Compartmentalization of Reciprocal Synapses

Reciprocal synapses are formed by neighboring dendritic processes that create the smallest possible neural circuit. Reciprocal synapses are widespread in brain and essential for information processing, but constitute a conceptual conundrum: How are adjacent pre- and post-synaptic specializations maintained as separate functional units? Here, we reveal an organizational principle for reciprocal synapses, using dendrodendritic synapses between mitral and granule cells in the mouse olfactory bulb as a paradigm. We show that mitral cells secrete cerebellin-1 to block the cis-interaction of mitral cell neurexins with neuroligins, thereby enabling their separate trans-interactions. Ablating either cerebellin-1 or neuroligins in mitral cells severely impaired granule cell[->]mitral cell synapses, as did overexpression of postsynaptic neurexins that form cis-complexes with neuroligins, but not of mutant neurexins unable to bind to neuroligins. Our data uncover a cis/trans-protein interaction network as a general design principle that organizes reciprocal dendro-dendritic synapses by compartmentalizing neurexin-based trans-synaptic protein complexes.

neuroscience↗

bioRxiv2020

Astrocytic Neurexin-1 Orchestrates Functional Synapse Assembly

At tripartite synapses, astrocytes enmesh synaptic contacts, but how astrocytes contribute to the formation, maturation and plasticity of synapses remains elusive. Here we show that both astrocytes and neurons abundantly express neurexin-1, a presynaptic adhesion molecule that controls synaptic properties. Using super-resolution imaging, we demonstrate that presynaptic neuronal and astrocytic neurexin-1 form discrete nanoclusters at excitatory synapses. We find that distinct patterns of heparan sulfate modification and alternative splicing confer onto astrocytic and neuronal neurexin-1 different ligand specificities, thereby enabling compartment-specific signaling by neurexin-1. At hippocampal Schaffer-collateral synapses, deletion of neurexin-1 from either astrocytes or neurons did not alter synapse numbers, but differentially impaired synapse function. Neuronal neurexin-1 was essential for NMDA-receptor-mediated synaptic responses, whereas astrocytic neurexin-1 was required for maturation of silent synapses, AMPA-receptor recruitment, and long-term potentiation. Thus, astrocytes and neurons surprisingly use the same synaptic adhesion molecule to control distinct synapse properties.

neuroscience↗