Neuron最新文献

Puberty onset in mammals requires adequate energy stores, but how hypothalamic neurons regulating reproduction obtain information on food availability is unclear. In this issue of Neuron, Goto et al.¹ show that hypothalamic neurons expressing agouti-related peptides, which are hunger sensors, control the maturation of kisspeptin neurons, the principal stimulators of reproduction.

Neurons are long-lived postmitotic cells that capitalize on autophagy to remove toxic or defective proteins and organelles to maintain neurotransmission and the integrity of their functional proteome. Mutations in autophagy genes cause congenital diseases, sharing prominent brain dysfunctions including epilepsy, intellectual disability, and neurodegeneration. Ablation of core autophagy genes in neurons or glia disrupts normal behavior, leading to motor deficits, memory impairment, altered sociability, and epilepsy, which are associated with defects in synapse maturation, plasticity, and neurotransmitter release. In spite of the importance of autophagy for brain physiology, the substrates of neuronal autophagy and the mechanisms by which defects in autophagy affect synaptic function in health and disease remain controversial. Here, we summarize the current state of knowledge on neuronal autophagy, address the existing controversies and inconsistencies in the field, and provide a roadmap for future research on the role of autophagy in the control of synaptic function.

Discrete activation of N-methyl-D-aspartate receptor (NMDAR) subtypes by glutamate and the co-agonist glycine is fundamental to neuroplasticity. A distinct variant, the tri-heteromeric receptor, comprising glycine-binding GluN1 and two types of glutamate-binding GluN2 subunits, exhibits unique pharmacological characteristics, notably enhanced sensitivity to the anti-depressant channel blocker S-(+)-ketamine. Despite its significance, the structural mechanisms underlying ligand gating and channel blockade of tri-heteromeric NMDARs remain poorly understood. Here, we identify and characterize tri-heteromeric GluN1-2B-2D NMDAR in the adult brain, resolving its structures in the activated, inhibited, and S-(+)-ketamine-blocked states. These structures reveal the ligand-dependent conformational dynamics that modulate the tension between the extracellular domain and transmembrane channels, governing channel gating and blockade. Additionally, we demonstrate that the inhibitor (S)-DQP-997-74 selectively decouples linker tension in GluN2D, offering insights into subtype-selective targeting for cognitive modulation.

The enteric nervous system is comprised of interconnected diverse cell types that control sensory and motor functions of the gut. In this issue of Neuron, Hamnett et al. demonstrate a novel role for distinct glutamatergic putative interneuron subtypes in colonic motility.

Integrating analyses of genetically defined cell types with population-level approaches remains poorly explored. We investigated this question by focusing on hippocampal spatial maps and the contribution of two genetically defined pyramidal cell types in the deep and superficial CA1 sublayers. Using single- and dual-color miniscope imaging in mice running along a linear track, we found that population activity from these cells exhibited three-dimensional ring manifolds that encoded the animal position and running direction. Despite shared topology, sublayer-specific manifolds displayed distinct geometric features. Manipulating track orientation revealed rotational and translational changes in manifolds from deep cells, contrasting with more stable representations by superficial cells. These transformations were not observed in manifolds derived from the entire CA1 population. Instead, cell-type-specific chemogenetic silencing of either sublayer revealed independent geometric codes. Our results show how genetically specified subpopulations may underpin parallel spatial maps that can be manipulated independently.

NMDARs act as coincidence detectors for synaptic plasticity by activity-dependent relief of Mg²⁺ pore block. In this issue of Neuron, Huang et al. solved the structure of NMDARs to enlighten the fascinating actions of Mg²⁺ beyond its pore binding.¹.

Hippocampal place cells have single, bell-shaped place fields in small environments. Recent experiments, however, reveal that, in large environments, place cells have multiple fields with heterogeneous shapes and sizes. We show that this diversity is explained by a surprisingly simple mathematical model, in which place fields are generated by thresholding a realization of a random Gaussian process. The model captures the statistics of field arrangements and generates new quantitative predictions about the statistics of field shapes and topologies. These predictions are quantitatively verified in bats and rodents, in one, two, and three dimensions, in both small and large environments. These results imply that common mechanisms underlie the diverse statistics observed in different experiments and further suggest that synaptic projections to CA1 are predominantly random.

The rather abstract mathematical study of place cell statistics by Mainali et al., in this issue of Neuron, may in fact help deliver us from the clutches of prejudiced functionalist assumptions, helping us better appreciate how the brain takes in nature in its chaotic, random manifestations.