THE ROLE OF UBIQUITIN LIGASE ADAPTOR PROTEIN NDFIP1 IN NEURONAL DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$581,813.00
Summary
Many brain diseases are characterized by faulty connections between nerve cells (neurons), in some cases caused by the inability to remove unwanted proteins from the neuron. This function is carried out by the ubiquitin-proteasome system (UPS). We have evidence that a UPS protein called Ndfip1 is important for forming functional brain circuits. We aim to discover whether neuron growth, branching and connectivity is promoted by Ndfip1 targeting of PTEN (phosphatase with tensin homology) to the UP ....Many brain diseases are characterized by faulty connections between nerve cells (neurons), in some cases caused by the inability to remove unwanted proteins from the neuron. This function is carried out by the ubiquitin-proteasome system (UPS). We have evidence that a UPS protein called Ndfip1 is important for forming functional brain circuits. We aim to discover whether neuron growth, branching and connectivity is promoted by Ndfip1 targeting of PTEN (phosphatase with tensin homology) to the UPS.Read moreRead less
Investigating Action Potential Initiation And Propagation In Neurons Using Voltage-sensitive Dyes
Funder
National Health and Medical Research Council
Funding Amount
$317,076.00
Summary
Nerve impulses, or action potentials, are the fundamental electrical signals used by the nervous system for communication. Critical to an understanding of neuronal function is the knowledge of where these events are initiated and how they propagate. Furthermore, this knowledge is required for understanding what goes wrong under conditions where there is a disturbance in neuronal communication, as occurs in many neurological disorders such as multiple sclerosis and epilepsy.
Properties Of Dendritic Spines And Their Role In Synaptic Plasticity
Funder
National Health and Medical Research Council
Funding Amount
$336,767.00
Summary
Connections between nerve cells in the brain often occur onto enlarged protrusions called dendritic spines. This proposal will investigate the properties of dendritic spines, and relate differences in spine properties to synaptic plasticity. This information can be used to better understand and treat neurological disorders associated with spine malfunction, as occur in some forms of mental retardation, and may help with understanding the memory loss that occurs during ageing and dementia.
The research described in this Project Grant application should help to us understand how our brains make memories. Our brains contain billions of interconnected nerve cells forming unimaginable numbers of possible networks. Previous research indicates that repetitive activation of individual networks can lead to changes in the strength of connections between nerve cells. These changes in connection strength are thought to underlie learning and memory. The experiments described in this proposal ....The research described in this Project Grant application should help to us understand how our brains make memories. Our brains contain billions of interconnected nerve cells forming unimaginable numbers of possible networks. Previous research indicates that repetitive activation of individual networks can lead to changes in the strength of connections between nerve cells. These changes in connection strength are thought to underlie learning and memory. The experiments described in this proposal will address the mechanisms underlying changes in the strength of connections between nerve cells. As most of the inputs nerve cells receive from other nerve cells are made onto their dendrites (small branching processes that extend from the cell body), the main objective is to investigate the interactions at the dendritic level responsible for changes in connection strength. The results of this work will raise our understanding of how memories are formed, which will be essential if we are to understand the cellular processes disrupted during memory dysfunction in neurological disorders such as dementia.Read moreRead less
SEZ6 AND NEURONAL CALCIUM SIGNALLING IN SYNAPSE DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$617,685.00
Summary
Inappropriate development and function of neuronal circuits is a universal feature of neurological disorders of cognition such as Down syndrome, autism spectrum disorders and Fragile X mental retardation, epilepsy, schizophrenia and Alzheimer�s disease. In these diseases, neurons exhibit abnormal neuronal branches (dendrites) and abnormal connections on dendritic spines. This research is aimed at understanding the mechanisms controlling dendrite development that underpin proper neuronal wiring.
The neocortex is the region of the brain that underlies all cognitive functions. Mental disorders, such as schizophrenia, occur when the communication between nerve cells in the neocortex breaks down. We propose to make electrical measurements from the thin processes of neurons that receive input from widely separated neocortical areas to understand how areas of the neocortex are functionally interlinked, with the ultimate aim to identify how these processes are disturbed in mental disorders.
Mechanisms And Consequences Of Cholinergic Signaling In Neocortical Pyramidal Neurons
Funder
National Health and Medical Research Council
Funding Amount
$258,000.00
Summary
Dementia, including Alzheimer s Disease, represents the second highest non-fatal disease burden in Australia. Modern theories suggest that cognitive deficits associated with disorders such as Alzheimer s Disease result in part from impairment of the action of the neurotransmitter acetylcholine. Despite the obvious importance of acetylcholine in brain function, there is currently a lack of basic knowledge regarding how this chemical works at the cellular level. We have recently discovered that ac ....Dementia, including Alzheimer s Disease, represents the second highest non-fatal disease burden in Australia. Modern theories suggest that cognitive deficits associated with disorders such as Alzheimer s Disease result in part from impairment of the action of the neurotransmitter acetylcholine. Despite the obvious importance of acetylcholine in brain function, there is currently a lack of basic knowledge regarding how this chemical works at the cellular level. We have recently discovered that acetylcholine produces opposing phasic and tonic actions on the excitability of brain cells in the cortex. The data collected in this study will reveal the receptor type, intracellular signalling pathways, and ionic mechanisms through which acetylcholine influences information processing in the brain. Together, these results will provide a framework for understanding the biological basis by which acetylcholine influences cognitive function. This new knowledge will in turn increase our understanding of why dysfunction of this important neurotransmitter system leads to the functional deficits observed in Alzheimer s Disease and other forms of dementia, and will hopefully suggest new targets for therapeutic intervention.Read moreRead less
Sez-6 Signalling Mechanisms And Function In The Developing Neocortex
Funder
National Health and Medical Research Council
Funding Amount
$501,815.00
Summary
Over the course of evolution, the mammalian brain cortex has become disproportionately large with respect to other brain regions. The dramatic increase in processing power resulting from the increased neuronal number and connectivity in the cortex has enabled us to acquire functions that make us human, such as the use of language. In spite of the enormous difference in size between the brains of humans and those of mice, studies on cortical development in mice are relevant to humans since the or ....Over the course of evolution, the mammalian brain cortex has become disproportionately large with respect to other brain regions. The dramatic increase in processing power resulting from the increased neuronal number and connectivity in the cortex has enabled us to acquire functions that make us human, such as the use of language. In spite of the enormous difference in size between the brains of humans and those of mice, studies on cortical development in mice are relevant to humans since the organization of the cortex (thickness, layer patterning and regional specialization) is very similar in these two organisms, and indeed, in all mammals. A complex series of developmental events is required to produce a normal brain cortex. Malformations in the cortex occurring in human neurological disorders, including epilepsy and mental retardation, result from mutations in genes regulating crucial developmental processes. Failure of developing nerve cells to make the correct connections can result in these, or other, debilitating neurological conditions. We have evidence that a brain protein called Seizure-related gene 6 (Sez-6) regulates normal connectivity and function of neurons in the mature cortex. We will determine the molecular pathways used for signalling of Sez-6 and also investigate in detail the formation of connections between cortical neurons early in development and how these connections become aberrant in the absence of Sez-6 function.Read moreRead less
Discovering Molecules And Mechanisms Regulating Dendrite Formation
Funder
National Health and Medical Research Council
Funding Amount
$517,989.00
Summary
Dendrites are neuronal projections necessary to receive stimuli from other neurons or the external environment. Abnormalities in dendrite development associate with mental retardation and other human conditions such as Down syndrome, Rett syndrome and Fragile-X syndrome. The studies presented in this proposal, using the powerful genetic and molecular tools available for the nematode C. elegans, will provide new insight into the cellular and molecular mechanisms regulating dendrite development.