Cagla Eroglu | |
---|---|
Born | Ankara, Turkey |
Alma mater | Middle East Technical University, Ruprecht-Karls-Universität Heidelberg, European Molecular Biology Laboratory Heidelberg, Stanford University |
Known for | Discovery of astrocyte factors implicated in regulation of synaptogenesis |
Awards | 2019 Ruth and A. Morris Williams, Jr. Faculty Research Prize, 2018 Lead Principal Investigator of Chan Zuckerberg Initiative Neurodegeneration Challenge Network, 2010 Alfred P. Sloan Fellow |
Scientific career | |
Fields | Neuroscience, molecular biology |
Institutions | Duke University |
Cagla Eroglu is a Turkish neuroscientist and associate professor of cell biology and neurobiology at Duke University in Durham, North Carolina and an investigator with the Howard Hughes Medical Institute. Eroglu is also the director of graduate studies in cell and molecular biology at Duke University Medical Center. [1] Eroglu is a leader in the field of glial biology, and her lab focuses on exploring the role of glial cells, specifically astrocytes, in synaptic development and connectivity.
Eroglu was born in Turkey and pursued her bachelor's degree in chemical engineering from 1992 to 1996 at the Middle East Technical University in Ankara, Turkey. [2] After completing her B.Sc., Eroglu pursued a master's degree in molecular biology at the Bilkent Üniversitesi in Ankara, Turkey, in 1996. After completing her master's degree in 1998, Eroglu moved to Germany to pursue her graduate studies in molecular biology at Ruprecht-Karls-Universität Heidelberg in Germany. [3] Eroglu's Ph.D. was supported by the European Molecular Biology Laboratory Ph.D. program as she studied under the mentorship of Irmgard Sinning, whose lab moved from EMBL to Heidelberg University in 2000. [4] Eroglu's Ph.D. was broadly focused in the study of membrane proteins biology. Using drosophila as a model organism, Eroglu looked at how metabotropic glutamate receptor (mGluRs) affinity is modulated. [5] She found that when mGluRs are associated with cholesterol rich lipid rafts within the membrane, they exist in a high affinity state for glutamate. [5] When mGluRs are not associated with sterol-rich rafts, they exist in a low affinity state for glutamate binding. [5]
After completing her Ph.D. in 2002, Eroglu came to the United States to study under the mentorship of Ben Barres at Stanford University. [3] Eroglu began studying glial cells under Barres’ mentorship. Eroglu, along with her colleagues in the Barres Lab, brought to light the critical and understudied role glial cells play in shaping synapses and neural circuits during development. [6] Eroglu and her team found that an astrocyte derived factor, called Thrombospondin, is important in promoting synaptogenesis in the central nervous system. [7] Eroglu then characterized the receptor to which Thrombospondin binds, called α2δ-1, which happened to also be the receptor to which the drug gabapentin binds. [7] When they over-expressed α2δ-1, they found increases in synaptogenesis and when they blocked the receptor with gabapentin, they found markedly decreased excitatory synapse formation. [7] Her findings showed both the role that astrocyte secreted factors play in specifically excitatory synapse formation, as well as the potential therapeutic mechanism why which gabapentin is able to mediate analgesia and prevent seizures. [7] Another discovery that Eroglu made while in the Barres Lab was the identification and function of hevin and SPARC, two astrocyte-secreted proteins, in the regulation of excitatory synapse development. [8] She found that hevin induces the formation of synapses, while SPARC antagonizes the synaptogenic actions of hevin. [8] Her work further highlighted the critical role astrocytes play in the direct regulation of synapse formation in the central nervous system. [8] Eroglu completed her postdoctoral work in 2008. [3]
In 2008, Eroglu joined the faculty at Duke University as an associate professor in the department of cell biology and in the department of neuroscience. [10] Eroglu is also a Faculty Network Member of the Duke Institute for Brain Sciences, an associate of the Duke Initiative for Science and Society, an Affiliate of the Regeneration Next Initiative, as well as a member of the ALICE program within the Duke University School of Medicine. [11]
Eroglu's lab studies the mechanisms underlying synaptic connectivity in the central nervous system. [12] The lab focuses significantly on the cellular and molecular role astrocytes play in shaping synapse development, function, and plasticity. [12] Their focus on the communication between astrocytes and neurons in the healthy brain is paving the way towards eventually understanding how this communication becomes pathological in disease states and how it can be therapeutically targeted. [12]
Eroglu and her team sought to understand how synaptic connectivity was altered in models of Huntington's disease. [13] They directly probed the role of Huntingtin protein (htt) in synaptic connectivity and they found that when htt was silenced, excitatory synapses in the cortex and striatum formed at a rapid pace and then started to deteriorate shortly after their rapid development. [13] They then knocked-in the disease causing htt mutation and saw similar findings to when they knocked out htt suggesting that proper htt function is necessary for normal cortical and striatal development. [13]
After discovering hevin, the astrocyte secreted factor implicated in synapse development, in her postdoctoral work, Eroglu continued to explore its role in shaping cortical development in the mouse brain. [14] She found that, when hevin is knocked out, there are reductions in the thalamocortical synapses yet increases in excitatory connections within the cortex. [14] They further found that critical pruning of spines with multiple excitatory contacts fails to take place when hevin is knocked out. [14] These in vivo results emphasize the critical regulatory role played by the astrocytic factor, hevin, in normal cortical development. [14]
Eroglu and a team of researchers were interested in exploring the therapeutic potential of human Umbilical Tissue Derived cells (hUTCs) in synaptogenesis. [15] They found that hUTCs could support neural growth specifically through the release of thrombospondin. [15] A further in depth analysis into the role of thrombospondin and their receptors α2δ-1, which Eroglu discovered in her postdoc, highlighted the critical role signalling between thrombospondin and their receptors have in synaptogenesis. [16] Eroglu then found that specifically inhibiting postsynaptic α2δ-1 (thrombospondin receptors) on neurons leads to decreased synaptogenesis and spine formation. [16] They further show that the regulation of synaptogenesis is dependent on Rac1, suggesting its role in development and pathology. [16]
Within a nervous system, a neuron, neurone, or nerve cell is an electrically excitable cell that fires electric signals called action potentials across a neural network. Neurons communicate with other cells via synapses - specialized connections that commonly use minute amounts of chemical neurotransmitters to pass the electric signal from the presynaptic neuron to the target cell through the synaptic gap. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. Non-animals like plants and fungi do not have nerve cells. The ability to generate electric signals first appeared in evolution 700 million years ago. 800 million years ago, predecessors of neurons were the peptidergic secretory cells. They eventually gained new gene modules which enabled cells to create post-synaptic scaffolds and ion channels that generate fast electrical signals. The ability to generate electric signals was a key innovation in the evolution of the nervous system.
Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.
The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.
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.
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.
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.
Thrombospondins (TSPs) are a family of secreted glycoproteins with antiangiogenic functions. Due to their dynamic role within the extracellular matrix they are considered matricellular proteins. The first member of the family, thrombospondin 1 (THBS1), was discovered in 1971 by Nancy L. Baenziger.
An apical dendrite is a dendrite that emerges from the apex of a pyramidal cell. Apical dendrites are one of two primary categories of dendrites, and they distinguish the pyramidal cells from spiny stellate cells in the cortices. Pyramidal cells are found in the prefrontal cortex, the hippocampus, the entorhinal cortex, the olfactory cortex, and other areas. Dendrite arbors formed by apical dendrites are the means by which synaptic inputs into a cell are integrated. The apical dendrites in these regions contribute significantly to memory, learning, and sensory associations by modulating the excitatory and inhibitory signals received by the pyramidal cells.
Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.
Ben A. Barres was an American neurobiologist at Stanford University. His research focused on the interaction between neurons and glial cells in the nervous system. Beginning in 2008, he was chair of the Neurobiology Department at Stanford University School of Medicine. He transitioned to male in 1997, and became the first openly transgender scientist in the National Academy of Sciences in 2013.
The synaptotropic hypothesis, also called the synaptotrophic hypothesis, is a neurobiological hypothesis of neuronal growth and synapse formation. The hypothesis was first formulated by J.E. Vaughn in 1988, and remains a focus of current research efforts. The synaptotropic hypothesis proposes that input from a presynaptic to a postsynaptic cell eventually can change the course of synapse formation at dendritic and axonal arbors. This synapse formation is required for the development of neuronal structure in the functioning brain.
Glutamate [NMDA] receptor subunit epsilon-2, also known as N-methyl D-aspartate receptor subtype 2B, is a protein that in humans is encoded by the GRIN2B gene.
Neuroligin (NLGN), a type I membrane protein, is a cell adhesion protein on the postsynaptic membrane that mediates the formation and maintenance of synapses between neurons. Neuroligins act as ligands for β-neurexins, which are cell adhesion proteins located presynaptically. Neuroligin and β-neurexin "shake hands", resulting in the connection between two neurons and the production of a synapse. Neuroligins also affect the properties of neural networks by specifying synaptic functions, and they mediate signalling by recruiting and stabilizing key synaptic components. Neuroligins interact with other postsynaptic proteins to localize neurotransmitter receptors and channels in the postsynaptic density as the cell matures. Additionally, neuroligins are expressed in human peripheral tissues and have been found to play a role in angiogenesis. In humans, alterations in genes encoding neuroligins are implicated in autism and other cognitive disorders. Antibodies in a mother from previous male pregnancies against neuroligin 4 from the Y chromosome increase the probability of homosexuality in male offspring.
Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.
In neuroscience, synaptic scaling is a form of homeostatic plasticity, in which the brain responds to chronically elevated activity in a neural circuit with negative feedback, allowing individual neurons to reduce their overall action potential firing rate. Where Hebbian plasticity mechanisms modify neural synaptic connections selectively, synaptic scaling normalizes all neural synaptic connections by decreasing the strength of each synapse by the same factor, so that the relative synaptic weighting of each synapse is preserved.
Gabapentinoids, also known as α2δ ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) which block α2δ subunit-containing voltage-dependent calcium channels (VDCCs). This site has been referred to as the gabapentin receptor, as it is the target of the drugs gabapentin and pregabalin.
In neuroscience, glutamate is the anion of glutamic acid in its role as a neurotransmitter. 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.
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.
Nicola J. Allen is a British neuroscientist. Allen studies the role of astrocytes in brain development, homeostasis, and aging. Her work uncovered the critical roles these cells play in brain plasticity and disease. Allen is currently an associate professor at the Salk Institute for Biological Studies and Hearst Foundation Development Chair.
Brain cells make up the functional tissue of the brain. The rest of the brain tissue is structural or connective called the stroma which includes blood vessels. The two main types of cells in the brain are neurons, also known as nerve cells, and glial cells, also known as neuroglia.