NGLY1 mutations cause protein aggregation in human neurons.

Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy, and seizures. NGLY1's activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.

Effective and efficient neural networks for spike inference from in vivo calcium imaging.

Calcium imaging provides advantages in monitoring large populations of neuronal activities simultaneously. However, it lacks the signal quality provided by neural spike recording in traditional electrophysiology. To address this issue, we developed a supervised data-driven approach to extract spike information from calcium signals. We propose the ENS2 (effective and efficient neural networks for spike inference from calcium signals) system for spike-rate and spike-event predictions using ΔF/F0 calcium inputs based on a U-Net deep neural network. When testing on a large, ground-truth public database, it consistently outperformed state-of-the-art algorithms in both spike-rate and spike-event predictions with reduced computational load. We further demonstrated that ENS2 can be applied to analyses of orientation selectivity in primary visual cortex neurons. We conclude that it would be a versatile inference system that may benefit diverse neuroscience studies.

Heterosynaptic Plasticity and the Experience-Dependent Refinement of Developing Neuronal Circuits.

Neurons remodel the structure and strength of their synapses during critical periods of development in order to optimize both perception and cognition. Many of these developmental synaptic changes are thought to occur through synapse-specific homosynaptic forms of experience-dependent plasticity. However, homosynaptic plasticity can also induce or contribute to the plasticity of neighboring synapses through heterosynaptic interactions. Decades of research in vitro have uncovered many of the molecular mechanisms of heterosynaptic plasticity that mediate local compensation for homosynaptic plasticity, facilitation of further bouts of plasticity in nearby synapses, and cooperative induction of plasticity by neighboring synapses acting in concert. These discoveries greatly benefited from new tools and technologies that permitted single synapse imaging and manipulation of structure, function, and protein dynamics in living neurons. With the recent advent and application of similar tools for in vivo research, it is now feasible to explore how heterosynaptic plasticity contribute to critical periods and the development of neuronal circuits. In this review, we will first define the forms heterosynaptic plasticity can take and describe our current understanding of their molecular mechanisms. Then, we will outline how heterosynaptic plasticity may lead to meaningful refinement of neuronal responses and observations that suggest such mechanisms are indeed at work in vivo. Finally, we will use a well-studied model of cortical plasticity-ocular dominance plasticity during a critical period of visual cortex development-to highlight the molecular overlap between heterosynaptic and developmental forms of plasticity, and suggest potential avenues of future research.