Loss of TDP-43 function underlies hippocampal and cortical synaptic deficits in TDP-43 proteinopathies.

TDP-43 proteinopathy is linked to neurodegenerative diseases that feature synaptic loss in the cortex and hippocampus, although it remains unclear how TDP-43 regulates mature synapses. We report that, in adult mouse hippocampus, TDP-43 knockdown, but not overexpression, induces robust structural and functional damage to excitatory synapses, supporting a role for TDP-43 in maintaining mature synapses. Dendritic spine loss induced by TDP-43 knockdown is rescued by wild-type TDP-43, but not ALS/FTLD-associated mutants, suggesting a common TDP-43 functional deficiency in neurodegenerative diseases. Interestingly, M337V and A90V mutants also display dominant negative activities against WT TDP-43, partially explaining why M337V transgenic mice develop hippocampal degeneration similar to that in excitatory neuronal TDP-43 knockout mice, and why A90V mutation is associated with Alzheimer's disease. Further analyses reveal that a TDP-43 knockdown-induced reduction in GluN2A contributes to synaptic loss. Our results show that loss of TDP-43 function underlies hippocampal and cortical synaptic degeneration in TDP-43 proteinopathies.

Differential depletion of GluN2A induces heterogeneous schizophrenia-related phenotypes in mice.

BACKGROUND: Schizophrenia, a debilitating psychiatric disorder, displays considerable interindividual variation in clinical presentations. The ongoing debate revolves around whether this heterogeneity signifies a continuum of severity linked to a singular causative factor or a collection of distinct subtypes with unique origins. Within the realm of schizophrenia, the functional impairment of GluN2A, a subtype of the NMDA receptor, has been associated with an elevated risk. Despite GluN2A's expression across various neuronal types throughout the brain, its specific contributions to schizophrenia and its involvement in particular cell types or brain regions remain unexplored. METHODS: We generated age-specific, cell type-specific or brain region-specific conditional knockout mice targeting GluN2A and conducted a comprehensive analysis using tests measuring phenotypes relevant to schizophrenia. FINDINGS: Through the induction of germline ablation of GluN2A, we observed the emergence of numerous schizophrenia-associated abnormalities in adult mice. Intriguingly, GluN2A knockout performed at different ages, in specific cell types and within distinct brain regions, we observed overlapping yet distinct schizophrenia-related phenotypes in mice. INTERPRETATION: Our interpretation suggests that the dysfunction of GluN2A is sufficient to evoke heterogeneous manifestations associated with schizophrenia, indicating that GluN2A stands as a prominent risk factor and a potential therapeutic target for schizophrenia. FUNDING: This project received support from the Shanghai Municipal Science and Technology Major Project (Grant No. 2019SHZDZX02) awarded to Y.C. and the Natural Science Foundation of Shanghai (Grant No. 19ZR1468600 and 201409003800) awarded to G.Y.

GluN2A mediates ketamine-induced rapid antidepressant-like responses.

Ketamine was thought to induce rapid antidepressant responses by inhibiting GluN2B-containing N-methyl-D-aspartic acid (NMDA) receptors (NMDARs), which presents a promising opportunity to develop better antidepressants. However, adverse side effects limit the broader application of ketamine and GluN2B inhibitors are yet to be approved for clinical use. It is unclear whether ketamine acts solely through GluN2B-dependent mechanisms. The present study reports that the loss of another major NMDAR subunit, GluN2A, in adult mouse brains elicits robust antidepressant-like responses with limited impact on the behaviors that mimic the psychomimetic effects of ketamine. The antidepressant-like behavioral effects of broad NMDAR channel blockers, such as ketamine and MK-801 (dizocilpine), were mediated by the suppression of GluN2A, but not by the inhibition of GluN2B. Moreover, treatment with ketamine or MK-801 rapidly increased the intrinsic excitability of hippocampal principal neurons through GluN2A, but not GluN2B. Together, these findings indicate that GluN2A mediates ketamine-triggered rapid antidepressant-like responses.

NMDA receptor-dependent prostaglandin-endoperoxide synthase 2 induction in neurons promotes glial proliferation during brain development and injury.

Astrocytes play critical roles in brain development and disease, but the mechanisms that regulate astrocyte proliferation are poorly understood. We report that astrocyte proliferation is bi-directionally regulated by neuronal activity via NMDA receptor (NMDAR) signaling in neurons. Prolonged treatment with an NMDAR antagonist reduced expression of cell-cycle-related genes in astrocytes in hippocampal cultures and suppressed astrocyte proliferation in vitro and in vivo, whereas neuronal activation promoted astrocyte proliferation, dependent on neuronal NMDARs. Expression of prostaglandin-endoperoxide synthase 2 (Ptgs2) is induced specifically in neurons by NMDAR activation and is required for activity-dependent astrocyte proliferation through its product, prostaglandin E2 (PGE2). NMDAR inhibition or Ptgs2 genetic ablation in mice reduced the proliferation of astrocytes and microglia induced by mild traumatic brain injury in the absence of secondary excitotoxicity-induced neuronal death. Our study defines an NMDAR-mediated signaling mechanism that allows trans-cellular control of glial proliferation by neurons in brain development and injury.

Substitution of copper atoms into defect-rich molybdenum sulfides and their electrocatalytic activity.

Studies on intercalation or substitution of atoms into layered two-dimensional (2D) materials are rapidly expanding and gaining significant consideration due to their importance in electronics, catalysts, batteries, sensors, etc. In this manuscript, we report a straightforward method to create sulphur (S) deficient molybdenum (Mo) sulfide (MoS2-x ) structures and substitute them with zerovalent copper (Cu) atoms using a colloidal synthesis method. The synthesized materials were studied using several techniques to understand the proportion and position of copper atoms and the effect of copper functionalization. Specifically, the impact of change in the ratio of Cu : S and the hydrogen evolution reaction (HER) activity of the derived materials were evaluated. This technique paves the way for the synthesis of various functionalized 2D materials with a significant impact on their physical and chemical behavior making them potential candidates for catalysis and several other applications such as energy storage and the development of numerous functional devices.