Biology subjects

Rau, A. R.

Publications and source records attributed to Rau, A. R..

3 recordsLinked to original sources

bioRxiv2025

UCM-A86 is a selective positive allosteric modulator of GluN1/GluN3 NMDA receptors

N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission in the central nervous system (CNS) where they play critical roles in normal and pathological brain functions and neurodevelopment. While the glutamate/glycine-activated GluN2-containing NMDA receptors (GluN1/GluN2) have been extensively studied, the physiological roles and pharmacology of glycine-activated GluN3-containing receptors (GluN1/GluN3) remain less understood. Although GluN1/GluN3 receptors exhibit unique functional properties and play distinct roles in neuronal development and synapse maturation, studies of their precise roles in neurophysiology and circuit function are impeded by limited availability of GluN3-selective pharmacological tools. This study describes UCM-A86, a novel GluN3-selective positive allosteric modulator, with EC50 values of 21 {micro}M and 19 {micro}M at GluN1/GluN3A and GluN1/GluN3B receptors, respectively. UCM-A86 selectively potentiates recombinant GluN1/GluN3A and GluN1/GluN3B receptors by 436% and 174%, respectively, relative to activation by glycine, with no activity at recombinant GluN1/GluN2A-D receptors. Furthermore, UCM-A86 selectively potentiates responses from native GluN1/GluN3A receptors expressed in somatostatin-expressing interneurons of the somatosensory cortex with no modulation of hippocampal AMPA receptor- and GluN1/2 NMDA receptor-mediated excitatory postsynaptic currents. Mechanistic studies suggest that UCM-A86 modulation is facilitated by agonist binding (or channel gating) and that UCM-A86 primarily potentiates GluN1/GluN3A by increasing open probability with no effects on mean channel conductance. These findings advance the synthetic pharmacology of GluN1/GluN3 receptors and provide a novel tool for modulation of native GluN3-containing NMDA receptors. Significance statementThis study introduces UCM-A86 as the first positive allosteric modulator selective for GluN3-containing NMDA receptors, addressing a critical gap in the pharmacological toolbox for investigating these understudied receptor subtypes. Using electrophysiological approaches in both recombinant and native systems, UCM-A86 demonstrates specific modulation of GluN3-containing NMDA receptors without affecting GluN2-containing NMDA receptors or AMPA receptors. UCM-A86 therefore provides new avenues to investigate the physiological roles of GluN3 subunits in normal and pathological brain function.

neuroscience↗

bioRxiv2023

Mutagenic-end joining results in smaller deletions in heterochromatin relative to euchromatin

Pericentromeric heterochromatin is highly enriched for repetitive sequences prone to aberrant recombination. Previous studies showed that homologous recombination (HR) repair is uniquely regulated in this domain to enable safe repair while preventing aberrant recombination. In Drosophila cells, DNA double-strand breaks (DSBs) relocalize to the nuclear periphery through nuclear actin-driven directed motions before recruiting the strand invasion protein Rad51 and completing HR repair. End-joining (EJ) repair also occurs with high frequency in heterochromatin of fly tissues, but how alternative EJ (alt-EJ) pathways operate in heterochromatin remains largely uncharacterized. Here, we induce DSBs in single euchromatic and heterochromatic sites using a new system that combines the DR-white reporter and I-SceI expression in spermatogonia of flies. Using this approach, we detect higher frequency of HR repair in heterochromatin, relative to euchromatin. Further, sequencing of mutagenic repair junctions reveals the preferential use of different EJ pathways across distinct euchromatic and heterochromatic sites. Interestingly, synthesis-dependent microhomology-mediated end joining (SD-MMEJ) appears differentially regulated in the two domains, with a preferential use of motifs close to the cut site in heterochromatin relative to euchromatin, resulting in smaller deletions. Together, these studies establish a new approach to study repair outcomes in fly tissues, and support the conclusion that heterochromatin uses more HR and less mutagenic EJ repair relative to euchromatin.

cell biology↗

bioRxiv2021

Ventral tegmental area glutamate neurons mediate the nonassociative consequences of traumatic stress

Exposure to trauma is a risk factor for the development of a number of mood disorders, and may enhance vulnerability to future adverse life events. Recent data implicate ventral tegmental area (VTA) glutamate neuronal activity as functionally important for signaling aversive or threating stimuli. However, it is unknown whether VTA glutamate neurons regulate transsituational outcomes that result from stress and whether these neurons are sensitive to stressor controllability. This work established an operant mouse paradigm to examine the impact of stressor controllability on VTA glutamate neuron function and stressor outcome. Uncontrollable (inescapable) stress, but not physically identical controllable (escapable) stress, produced social avoidance in male mice. Cell-type-specific calcium recordings showed that both controllable and uncontrollable stressors increased VTA glutamate neuronal activity. Chemogenetic reduction of VTA glutamate neuron activity prevented the behavioral sequelae of uncontrollable stress. Our results provide causal evidence that mice can be used to model stressor controllability and that VTA glutamate neurons may contribute to transsituational stressor outcomes, such as social avoidance and exaggerated fear that are observed within trauma-related disorders.

neuroscience↗