Nicotinamide adenine dinucleotide (NAD(+)) is an enzyme cofactor or cosubstrate in many essential biological pathways. To date, the primary source of neuronal NAD(+) has been unclear. NAD(+) can be synthesized from several different precursors, among which nicotinamide is the substrate predominantly used in mammals. The rate-limiting step in the NAD(+) biosynthetic pathway from nicotinamide is performed by nicotinamide phosphoribosyltransferase (Nampt). Here, we tested the hypothesis that neurons use intracellular Nampt-mediated NAD(+) biosynthesis by generating and evaluating mice lacking Nampt in forebrain excitatory neurons (CaMKIIαNampt(-/-) mice). CaMKIIαNampt(-/-) mice showed hippocampal and cortical atrophy, astrogliosis, microgliosis, and abnormal CA1 dendritic morphology by 2-3 months of age. Importantly, these histological changes occurred with altered intrahippocampal connectivity and abnormal behavior; including hyperactivity, some defects in motor skills, memory impairment, and reduced anxiety, but in the absence of impaired sensory processes or long-term potentiation of the Schaffer collateral pathway. These results clearly demonstrate that forebrain excitatory neurons mainly use intracellular Nampt-mediated NAD(+) biosynthesis to mediate their survival and function. Studying this particular NAD(+) biosynthetic pathway in these neurons provides critical insight into their vulnerability to pathophysiological stimuli and the development of therapeutic and preventive interventions for their preservation.
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http://dx.doi.org/10.1523/JNEUROSCI.4730-13.2014 | DOI Listing |
Front Neurol
December 2024
Department of Pediatrics, Peking University First Hospital, Beijing, China.
Introduction: Neonatal seizures are the most common clinical manifestation of neurological dysfunction in newborns, with an incidence ranging from 1 to 5‰. However, the therapeutic efficacy of current pharmacological treatments remains suboptimal. This study aims to utilize genetically modified hamsters with hypertriglyceridaemia (HTG) to investigate the effects of elevated triglycerides on neuronal excitability and to elucidate the underlying mechanisms.
View Article and Find Full Text PDFRegen Ther
March 2025
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
Introduction: Tau protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) and in regulating neuronal excitability. Among tau-coding microtubule associated protein tau () gene mutations, the A152T mutation is reported to increase the risk of AD and neuronal excitability in mouse models.
Methods: To investigate the effects of gene expression and its mutations on neuronal activity in human neurons, we employed genome editing technology to introduce the A152T or P301S mutations into induced pluripotent stem cells (iPSCs).
ACS Appl Mater Interfaces
January 2025
School of Information Science and Technology, Fudan University, Shanghai 200433, China.
To date, various kinds of memristors have been proposed as artificial neurons and synapses for neuromorphic computing to overcome the so-called von Neumann bottleneck in conventional computing architectures. However, related working principles are mostly ascribed to randomly distributed conductive filaments or traps, which usually lead to high stochasticity and poor uniformity. In this work, a heterostructure with a two-dimensional WS monolayer and a ferroelectric PZT film were demonstrated for memristors and artificial synapses, triggered by in-plane ferroelectric polarization.
View Article and Find Full Text PDFPLoS Comput Biol
January 2025
Department of Mathematics and Statistics, Middlebury College, Middlebury, Vermont, United States of America.
Chronic pain is a wide-spread condition that is debilitating and expensive to manage, costing the United States alone around $600 billion in 2010. In a common symptom of chronic pain called allodynia, non-painful stimuli produce painful responses with highly variable presentations across individuals. While the specific mechanisms remain unclear, allodynia is hypothesized to be caused by the dysregulation of excitatory-inhibitory (E-I) balance in pain-processing neural circuitry in the dorsal horn of the spinal cord.
View Article and Find Full Text PDFCell Rep
January 2025
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea; Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul 03080, South Korea; Transplantation Research Institute, Medical Research Center, Seoul National University, Seoul 03080, South Korea. Electronic address:
Cd99 molecule-like 2 (Cd99l2) is a type I transmembrane protein that plays a role in the transmigration of leukocytes across vascular endothelial cells. Despite its high expression in the brain, the role of Cd99l2 remains elusive. We find that Cd99l2 is expressed primarily in neurons and positively regulates neurite outgrowth and the development of excitatory synapses.
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