Biology subjects

Roberts, J. P.

Publications and source records attributed to Roberts, J. P..

4 recordsLinked to original sources

bioRxiv2023

The autism-associated loss of δ-catenin functions disrupts social behaviors

{delta}-catenin is expressed in excitatory synapses and functions as an anchor for the glutamatergic AMPA receptor (AMPAR) GluA2 subunit in the postsynaptic density. The glycine 34 to serine (G34S) mutation in the{delta} -catenin gene is found in autism spectrum disorder (ASD) patients and induces loss of {delta}-catenin functions at excitatory synapses, which is presumed to underlie ASD pathogenesis in humans. However, how the G34S mutation causes loss of {delta}-catenin functions to induce ASD remains unclear. Here, using neuroblastoma cells, we discover that the G34S mutation generates an additional phosphorylation site for glycogen synthase kinase 3{beta} (GSK3{beta}). This promotes {delta}-catenin degradation and causes the reduction of {delta}-catenin levels, which likely contributes to the loss of {delta}-catenin functions. Synaptic {delta}-catenin and GluA2 levels in the cortex are significantly decreased in mice harboring the {delta}-catenin G34S mutation. The G34S mutation increases glutamatergic activity in cortical excitatory neurons while it is decreased in inhibitory interneurons, indicating changes in cellular excitation and inhibition. {delta}-catenin G34S mutant mice also exhibit social dysfunction, a common feature of ASD. Most importantly, inhibition of GSK3{beta} activity reverses the G34S-induced loss of {delta}-catenin function effects in cells and mice. Finally, using {delta}-catenin knockout mice, we confirm that {delta}-catenin is required for GSK3{beta} inhibition-induced restoration of normal social behaviors in {delta}-catenin G34S mutant animals. Taken together, we reveal that the loss of {delta}-catenin functions arising from the ASD-associated G34S mutation induces social dysfunction via alterations in glutamatergic activity and that GSK3{beta} inhibition can reverse {delta}-catenin G34S-induced synaptic and behavioral deficits. Significance Statement{delta}-catenin is important for the localization and function of glutamatergic AMPA receptors at synapses in many brain regions. The glycine 34 to serine (G34S) mutation in the{delta} -catenin gene is found in autism patients and results in the loss of {delta}-catenin functions. {delta}-catenin expression is also closely linked to other autism-risk genes involved in synaptic structure and function, further implying that it is important for the autism pathophysiology. Importantly, social dysfunction is a key characteristic of autism. Nonetheless, the links between {delta}-catenin functions and social behaviors are largely unknown. The significance of the current research is thus predicated on filling this gap by discovering the molecular, cellular, and synaptic underpinnings of the role of {delta}-catenin in social behaviors.

neuroscience↗

bioRxiv2022

Entomopathogen-host evolution and implications for biopesticide resistance management

Insecticide resistance evolution is becoming increasingly problematic globally. With chemical insecticides, attempts to combat resistance involves developing compounds with novel modes of action, or increasing rates to overcome partial resistance. While pests can develop resistance to pathogens used as biopesticides, these "pesticides" can be subjected to evolutionary selection pressure as well and may be able to adapt countermeasures to overcome pest resistance. Here, we consider two scenarios: 1) a single trait governs an arms race between pest and parasite, and 2) an epidemiological scenario where each, pathogen transmission and virulence, are governed by host and pathogen traits. Considering the single-trait parasite attack scenario, the evolving parasite is able to overcome resistance in the pest population and effectively suppress host population abundance. In this case, overcoming biopesticide resistance may be possible from parasite evolution to resistant hosts. In contrast, when transmission and abundance are allowed to vary independently in an epidemiological model, different pathogen traits promote different types of resistance development in the host - more contagious pathogens promote pathogen-tolerant (low mortality susceptibility) hosts, while less contagious pathogens promote pathogen-resistant (low transmission susceptibility) hosts. Pathogen-tolerant hosts are particularly detrimental to control programs, because they can quickly outcompete wild types by promoting infection in wild type populations. Furthermore, because evolution of pathogen-tolerance in pests can benefit pathogens through increasing infection prevalence, we do not expect pathogen evolution to improve control. Thus, the keys to biopesticide management depend on the virulence-transmission trade-off and whether hosts evolve to better prevent or survive infection.

evolutionary biology↗

bioRxiv2020

Phosphorylation of AMPA receptor subunit GluA1 regulates clathrin-mediated receptor endocytosis

Synaptic strength is altered during synaptic plasticity by controlling the number of AMPA receptors (AMPARs) at excitatory synapses. In particular, during long-term potentiation and synaptic up-scaling, AMPARs are accumulated at synapses to increase synaptic strength. Neuronal activity leads to activity-dependent phosphorylation of AMPAR subunit GluA1, and subsequent increases in GluA1 surface expression, which can be achieved by either an increase in exocytosis or a decrease in endocytosis of the receptors. However, the molecular pathways underlying GluA1 phosphorylation-induced elevation of surface AMPAR expression are not completely understood. Here, we first employ fluorescence recovery after photobleaching (FRAP) to reveal that phosphorylation of GluA1 Serine 845 (S845) plays a more important role in receptor endocytosis than exocytosis during synaptic plasticity. Notably, endocytosis of AMPARs depends upon the clathrin adaptor, AP2, which recruits cargo proteins into endocytic clathrin coated pits. Importantly, the KRMK (Lysine-Arginine-Methionine-Lysine) motif in the carboxyl-terminus of GluA1 is suggested to be an AP2 binding site, but the exact function has not been defined. Moreover, the GluA1 KRMK motif is closely located to one of GluA1 phosphorylation sites, serine 845 (S845), and GluA1 S845 dephosphorylation is suggested to enhance endocytosis during long-term depression. In fact, we show that an increase in GluA1 S845 phosphorylation by two distinct forms of synaptic plasticity, long-term potentiation and synaptic up-scaling, diminishes the binding of the AP2 adaptor. This reduces endocytosis, resulting in elevation of GluA1 surface expression. We thus demonstrate a mechanism of GluA1 phosphorylation-regulated clathrin-mediated endocytosis of AMPARs.

neuroscience↗

bioRxiv2020

Selective co-activation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid-induced synaptic dysfunction

Beta-amyloid (A{beta}) has been recognized as an early trigger in the pathogenesis of Alzheimers disease (AD) leading to synaptic and cognitive impairments. A{beta} can alter neuronal signaling through interactions with nicotinic acetylcholine receptors (nAChRs), contributing to synaptic dysfunction in AD. The three major nAChR subtypes in the hippocampus are composed of 7-, 4{beta}2-, and 3{beta}4-nAChRs. A{beta} selectively affects 7- and 4{beta}2-nAChRs, but not 3{beta}4-nAChRs in hippocampal neurons, resulting in neuronal hyperexcitation. However, how nAChR subtype selectivity for A{beta} affects synaptic function in AD is not completely understood. Here, we showed that A{beta} associated with 7- and 4-containing nAChRs but not 3-containing receptors. Computational modeling suggested two amino acids in 7-nAChRs, Arginine 208 and Glutamate 211, were important for the interaction between A{beta} and 7-containing nAChRs. These residues were found to be conserved only in the 7 and 4 subunits. We therefore mutated these amino acids in 7-containing nAChRs to mimic the 3 subunit and found that mutant 7-containing receptors were unable to interact with A{beta}, providing direct molecular evidence for how A{beta} selectively interacted with 7- and 4-containing receptors, but not 3-containing nAChRs. Selective co-activation of 7- and 4{beta}2-nAChRs was also sufficient to reverse A{beta}-induced AMPA receptor (AMPAR) dysfunction, including A{beta}-induced reduction of AMPAR phosphorylation and surface expression in hippocampal neurons. Moreover, the A{beta}-induced disruption of long-term potentiation was reversed by co-stimulation of 7- and 4{beta}2-nAChRs. These findings support a novel mechanism for A{beta}s impact on synaptic function in AD, namely the differential regulation of nAChR subtypes.

neuroscience↗