Modifying Brain Excitabilty By Upregulating The KCC2 Chloride Transporter
Funder
National Health and Medical Research Council
Funding Amount
$535,662.00
Summary
Brain activity depends upon the fine balance between neuronal excitation and inhibition. When this balance is lost, debilitating seizures can result, such as occurs in epilepsy. We have developed a new gene manipulation approach to enhance neuronal inhibition and prevent seizures in mice. We will examine the physiological mechanisms underlying this effect, and we propose that we can also use this genetic switch to stop the progression into epilepsy that occurs following a brain trauma.
Role Of The Microglial Adaptor Molecule TYROBP In Alzheimer’s Disease Pathology
Funder
National Health and Medical Research Council
Funding Amount
$469,433.00
Summary
Immune activation characterizes Alzheimer’s disease (AD) brains; however, how it impacts AD progression is not understood. Our previous studies in AD brains identified the immune molecule TYROBP, pointing at both beneficial and detrimental effects triggered by this molecule. Here, we aim to understand in detail how TYROBP is involved in AD and how we can enhance its beneficial effects and decrease its unintended actions.
Interactions Between Developmental NMDA Receptor Dysfunction, Genetic Vulnerability And Early-life Stress In Schizophrenia: Studies Of Dysbindin Mutant Mice And Living Individuals At High Risk Of Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$347,457.00
Summary
This project will investigate two key pathways implicated in schizophrenia: glutamatergic (excitatory) neurotransmission and stress signalling. We will study how glutamatergic deficits emerge across postnatal development, in the presence or absence of early-life stress, in a schizophrenia-relevant mouse model, and investigate the interactions between stress and glutamatergic deficits in neuroepithelial cells from living individuals at high risk of schizophrenia.
Regulation Of Glutamate Receptor Trafficking By The Calcium- And Lipid-binding Protein, Copine-6
Funder
National Health and Medical Research Council
Funding Amount
$548,690.00
Summary
Abnormal levels of cell surface receptors in neurons can lead to a variety of debilitating neurological disorders and neurodegenerative diseases. These levels are tightly regulated through the orchestrated movements of receptors from inside the neuron to the cell surface. In this project we will examine how the transport of cell surface receptors is regulated by an intracellular signalling molecule, called copine, which is important in both epilepsy and Alzheimer’s disease.
Elucidating The Mechanisms Of Alpha-conotoxin-induced Calcium Channel Inhibition Via G Protein-coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$419,082.00
Summary
N-type voltage-gated calcium channels (VGCCs) are membrane proteins involved in neurotransmission and play a major role in pain. VGCCs are a well-established target for the development of analgesics. Our recent research identified that VGCCs can be inhibited by ?-conotoxins from the venom of marine snails by targeting ?-aminobutyric acid receptors in sensory neurons. We will characterize this novel form of modulation of VGCCs by ?-conotoxins and define the pathways that lead to VGCC inhibition.
Experience-dependent Cellular Plasticity And Cognitive Deficits In Mouse Models Of Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$444,318.00
Summary
Schizophrenia is a brain disorder involving psychiatric symptoms which include abnormalities of cognitive processes. We are using mouse models to understand the cause of cognitive deficits, at the level of molecules and cells. One discovery we have made is that the generation of new neurons, from adult neural stem cells, are abnormal in a specific brain region of these mice. This research will provide new information regarding the cause of cognitive deficits, and will have implications for the d ....Schizophrenia is a brain disorder involving psychiatric symptoms which include abnormalities of cognitive processes. We are using mouse models to understand the cause of cognitive deficits, at the level of molecules and cells. One discovery we have made is that the generation of new neurons, from adult neural stem cells, are abnormal in a specific brain region of these mice. This research will provide new information regarding the cause of cognitive deficits, and will have implications for the development of new treatments.Read moreRead less
Intra and intermolecular steps underpinning vesicular priming. This project aims to discover how secretory vesicles fuse with the plasma membrane, a process called priming. The fusion of secretory vesicles by exocytosis underpins neuronal communication. Despite efforts to understand vesicular fusion, how these vesicles become fusion-competent upon arrival at the plasma membrane is unknown. This project will use single molecule imaging to assess mobility changes of key priming molecules and uncov ....Intra and intermolecular steps underpinning vesicular priming. This project aims to discover how secretory vesicles fuse with the plasma membrane, a process called priming. The fusion of secretory vesicles by exocytosis underpins neuronal communication. Despite efforts to understand vesicular fusion, how these vesicles become fusion-competent upon arrival at the plasma membrane is unknown. This project will use single molecule imaging to assess mobility changes of key priming molecules and uncover their diffusional signature during priming. It intends to build a comprehensive model of molecular interactions that make a recently docked vesicle fusion-competent. This understanding is key to unravelling how the brain worksRead moreRead less
Mechanisms Guiding Pathfinding And Positioning Of Cortical Interneurons
Funder
National Health and Medical Research Council
Funding Amount
$621,606.00
Summary
Brain disorders place an economic and social burden on Australia and the personal costs of these illnesses are immeasurable. Several brain abnormalities are caused from the failure of neurons to position themselves in the correct location when the brain develops. Our study aims to discover how neurons move and what factors influence this process. It provides an understanding of normal brain development, as well as providing insight into what may go wrong in the formation of brain diseases.
DCC-Robo Interactions Cooperate To Regulate Callosal Axon Guidance
Funder
National Health and Medical Research Council
Funding Amount
$383,422.00
Summary
In order for the brain to function, the correct connections between neurons must be formed during development. These connections, formed by the axonal processes of neurons, are able to find their synaptic targets by sensing molecular cues within the brain that guide them, by attraction or repulsion, to their target. This proposal investigates how attractive and repulsive signals are received and integrated in neurons to enable axons to find their targets in the brain.
Mechanism Of Signal Transduction And Receptor Activation In Ligand Gated Ion Channel Receptors
Funder
National Health and Medical Research Council
Funding Amount
$551,560.00
Summary
This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. This knowledge is important since the Cys-loop family of ligand gated ion channel receptors are responsible for a wide range of neuronal signalling and the control of both excitatory and inhibitory receptors. The Cys-loop receptors are modulated by both therapeutic drugs (eg. benzodiazepines, barbiturates, antiemetics) and by recre ....This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. This knowledge is important since the Cys-loop family of ligand gated ion channel receptors are responsible for a wide range of neuronal signalling and the control of both excitatory and inhibitory receptors. The Cys-loop receptors are modulated by both therapeutic drugs (eg. benzodiazepines, barbiturates, antiemetics) and by recreational drugs (eg. alcohol, nicotine). They are also targets for development of new therapeutic drugs, such as allosteric modulators of nAChR for memory enhancement, or modulating GlyR to relieve spasticity or chronic pain. The project will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, gives rise to a number of neurological and psychiatric disease states. The ligand gated receptors are also major targets for therapeutic drugs and the information gained in this study may also provide insights into new ways in which drugs could be used to enhance or inhibit synaptic signalling.Read moreRead less