Proton-triggered rearrangement of the AMPA receptor N-terminal domains impacts receptor kinetics and synaptic localization.

AMPA glutamate receptors (AMPARs) are ion channel tetramers that mediate the majority of fast excitatory synaptic transmission. They are composed of four subunits (GluA1-GluA4); the GluA2 subunit dominates AMPAR function throughout the forebrain. Its extracellular N-terminal domain (NTD) determines receptor localization at the synapse, ensuring reliable synaptic transmission and plasticity. This synaptic anchoring function requires a compact NTD tier, stabilized by a GluA2-specific NTD interface. Here we show that low pH conditions, which accompany synaptic activity, rupture this interface. All-atom molecular dynamics simulations reveal that protonation of an interfacial histidine residue (H208) centrally contributes to NTD rearrangement. Moreover, in stark contrast to their canonical compact arrangement at neutral pH, GluA2 cryo-electron microscopy structures exhibit a wide spectrum of NTD conformations under acidic conditions. We show that the consequences of this pH-dependent conformational control are twofold: rupture of the NTD tier slows recovery from desensitized states and increases receptor mobility at mouse hippocampal synapses. Therefore, a proton-triggered NTD switch will shape both AMPAR location and kinetics, thereby impacting synaptic signal transmission.

A fully automated home cage for long-term continuous phenotyping of mouse cognition and behavior.

Automated home-cage monitoring systems present a valuable tool for comprehensive phenotyping of natural behaviors. However, current systems often involve complex training routines, water or food restriction, and probe a limited range of behaviors. Here, we present a fully automated home-cage monitoring system for cognitive and behavioral phenotyping in mice. The system incorporates T-maze alternation, novel object recognition, and object-in-place recognition tests combined with monitoring of locomotion, drinking, and quiescence patterns, all carried out over long periods. Mice learn the tasks rapidly without any need for water or food restrictions. Behavioral characterization employs a deep convolutional neural network image analysis. We show that combined statistical properties of multiple behaviors can be used to discriminate between mice with hippocampal, medial entorhinal, and sham lesions and predict the genotype of an Alzheimer's disease mouse model with high accuracy. This technology may enable large-scale behavioral screening for genes and neural circuits underlying spatial memory and other cognitive processes.

Cryo-EM structure of ssDNA bacteriophage ΦCjT23 provides insight into early virus evolution.

The origin of viruses remains an open question. While lack of detectable sequence similarity hampers the analysis of distantly related viruses, structural biology investigations of conserved capsid protein structures facilitate the study of distant evolutionary relationships. Here we characterize the lipid-containing ssDNA temperate bacteriophage ΦCjT23, which infects Flavobacterium sp. (Bacteroidetes). We report ΦCjT23-like sequences in the genome of strains belonging to several Flavobacterium species. The virion structure determined by cryogenic electron microscopy reveals similarities to members of the viral kingdom Bamfordvirae that currently consists solely of dsDNA viruses with a major capsid protein composed of two upright ß-sandwiches. The minimalistic structure of ΦCjT23 suggests that this phage serves as a model for the last common ancestor between ssDNA and dsDNA viruses in the Bamfordvirae. Both ΦCjT23 and the related phage FLiP infect Flavobacterium species found in several environments, suggesting that these types of viruses have a global distribution and a shared evolutionary origin. Detailed comparisons to related, more complex viruses not only expand our knowledge about this group of viruses but also provide a rare glimpse into early virus evolution.