 | A major contributor to this article appears to have a close connection with its subject.(October 2020) |
Hilmar Bading (born 1958) is a German physician and neuroscientist. He is a member of the German National Academy of Science Leopoldina [1] .
| A major contributor to this article appears to have a close connection with its subject.(October 2020) |
Hilmar Bading (born 1958) is a German physician and neuroscientist. He is a member of the German National Academy of Science Leopoldina [1] .
Hilmar Bading studied medicine from 1978 to 1984 at Heidelberg University (MD in 1984) and carried out his MD Thesis at the Max Planck Institute for Medical Research, Heidelberg on calcium transport ATPase in skeletal muscle. He received postdoctoral training at the Max Planck Institute for Molecular Genetics, Berlin, Germany (1985–1989) and at Harvard Medical School, Boston, US (1989–1993). From 1993 to 2001 he was a staff scientist at the MRC Laboratory of Molecular Biology, Cambridge, UK. Since 2001 he has been professor of neurobiology and director of the Neurobiology Institute and the Interdisciplinary Center for Neurosciences (IZN) at Heidelberg University. [2] [3]
He is co-founder of FundaMental Pharma GmbH, Heidelberg. [4]
He founded the Foundation BrainAid. [5]
Hilmar Bading's work is focused on neuronal calcium signaling and gene regulation in the nervous system. [6] He identified calcium as the principal second messenger in the coupling of neuronal activity to gene expression and characterized the processes that mediate the dialogue between the synapse and the nucleus. [7] [8] His work highlighted the spatial aspects of calcium signals [9] [10] and in particular the importance of nuclear calcium in governing activity-dependent gene expression and adaptations in the nervous system that include memory formation and acquired neuroprotection. [11] [12] [13] [14] The discovery of toxic signaling by extrasynaptic NMDA receptors which antagonizes gene regulation by synaptic activity and causes neuronal dysfunction and cell death [15] [16] contributed to the understanding of neurodegenerative disorders including Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). [15] [16] [17] [18] [19] [20]
Hilmar Bading and his co-workers uncovered the importance of a death signaling complex consisting of extrasynaptic NMDA receptors (NMDARs) and TRPM4 for excitotoxicity and identified a class of neuroprotective small molecules (known as NMDAR/TRPM4 interaction interface inhibitors or short ‚interface inhibitors‘) that disrupt the NMDAR/TRPM4 complex and protect against cell death in mouse models of stroke and retinal ganglion cell degeneration. [21]
2001: Wolfgang-Paul Prize of the Alexander von Humboldt Foundation [22]
2016: Innovation Prize of the German BioRegions [23]
2019: Elected to the German National Academy of Science Leopoldina [1]
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core was the first glutamate receptor ion channel domain to be crystallized.
The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.
In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.
In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.
In neuroscience, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane contains NMDA-type glutamate receptors but no AMPA-type glutamate receptors. These synapses are named "silent" because normal AMPA receptor-mediated signaling is not present, rendering the synapse inactive under typical conditions. Silent synapses are typically considered to be immature glutamatergic synapses. As the brain matures, the relative number of silent synapses decreases. However, recent research on hippocampal silent synapses shows that while they may indeed be a developmental landmark in the formation of a synapse, that synapses can be "silenced" by activity, even once they have acquired AMPA receptors. Thus, silence may be a state that synapses can visit many times during their lifetimes.
Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival of otherwise toxic levels of glutamate.
Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.
Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell.
Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells. They are usually induced from Ca2+ signaling, although recent research has questioned the role of Ca2+ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general.
Cystine/glutamate transporter is an antiporter that in humans is encoded by the SLC7A11 gene.
Long-term potentiation (LTP), thought to be the cellular basis for learning and memory, involves a specific signal transmission process that underlies synaptic plasticity. Among the many mechanisms responsible for the maintenance of synaptic plasticity is the cadherin–catenin complex. By forming complexes with intracellular catenin proteins, neural cadherins (N-cadherins) serve as a link between synaptic activity and synaptic plasticity, and play important roles in the processes of learning and memory.
In neuroscience, glutamate refers to the anion of glutamic acid in its role as a neurotransmitter: a chemical that nerve cells use to send signals to other cells. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.
Acquired neuroprotection is a synaptic-activity-dependent form of adaptation in the nervous system that renders neurons more resistant to harmful conditions. The term was coined by Hilmar Bading. This use-dependent enhancement of cellular survival activity requires changes in gene expression triggered by neuronal activity and nuclear calcium signaling. In rodents, components of the neuroprotective gene program can reduce brain damage caused by seizure-like activity or by a stroke. In acute and chronic neurodegenerative diseases, gene regulatory events important for acquired neuroprotection are antagonized by extrasynaptic NMDA receptor signaling leading to increased vulnerability, loss of structural integrity, and bioenergetics dysfunction.
The concentration of calcium in the cell nucleus can increase in response to signals from the environment. Nuclear calcium is an evolutionary conserved potent regulator of gene expression that allows cells to undergo long-lasting adaptive responses. The 'Nuclear Calcium Hypothesis’ by Hilmar Bading describes nuclear calcium in neurons as an important signaling end-point in synapse-to-nucleus communication that activates gene expression programs needed for persistent adaptations. In the nervous system, nuclear calcium is required for long-term memory formation, acquired neuroprotection, and the development of chronic inflammatory pain. In the heart, nuclear calcium is important for the development of cardiac hypertrophy. In the immune system, nuclear calcium is required for human T cell activation. Plants use nuclear calcium to control symbiosis signaling.
Extrasynaptic NMDA receptors are glutamate-gated neurotransmitter receptors that are localized to non-synaptic sites on the neuronal cell surface. In contrast to synaptic NMDA receptors that promote acquired neuroprotection and synaptic plasticity, extrasynaptic NMDA receptors are coupled to activation of death-signaling pathways. Extrasynaptic NMDA receptors are responsible for initiating excitotoxicity and have been implicated in the etiology of neurodegenerative diseases, including stroke, Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).
Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased expression of cytoskeletal and extracellular matrix elements and postsynaptic scaffold proteins, while pruning less active ones. For example, cell adhesion molecules (CAMs) play a large role in synaptic maintenance and stabilization. Gerald Edelman discovered CAMs and studied their function during development, which showed CAMs are required for cell migration and the formation of the entire nervous system. In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to learning and memory.
R. Suzanne Zukin is an American neuroscientist and a professor of neuroscience who directs a research lab as a F. M. Kirby Chair in Neural Repair and Protection and director of the Neuropsychopharmacology Center at Albert Einstein College of Medicine. Zukin's areas of research include neurodegenerative disorders, Ischemia, Epigenetics and Autism and uses molecular biology approaches to research these disorders. Zukin has made seminal contributions to the understanding of NMDA and AMPA receptor function and activity.
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