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.
Neurosteroid Modulation Of GABA-inhibition In Vivo: Central Auditory Pathway Models
Funder
National Health and Medical Research Council
Funding Amount
$331,650.00
Summary
All neurons at higher levels of the central nervous system signal in response to the outcome of various excitatory and inhibitory inputs (synapses) from other neurons. Most of the fast-acting inhibition is mediated by chloride ion influx through a channel which is gated by the neurotransmitter GABA. Termed the GABAa-receptor, this channel is known to be modulated by a wide range of pharmacological agents (e.g. valium; ethanol, many anaesthetics) which may enhance or suppress its efficacy. There ....All neurons at higher levels of the central nervous system signal in response to the outcome of various excitatory and inhibitory inputs (synapses) from other neurons. Most of the fast-acting inhibition is mediated by chloride ion influx through a channel which is gated by the neurotransmitter GABA. Termed the GABAa-receptor, this channel is known to be modulated by a wide range of pharmacological agents (e.g. valium; ethanol, many anaesthetics) which may enhance or suppress its efficacy. There are also good reasons for concluding that there is a capacity for modulation by endogenous substances. Brain synthesized steroids (neurosteroids) are known to have a potent enhancement effect upon the efficacy of GABAa-receptors, and have been implicated in a number of clinical situations, including menstrual cycle related depression. Work of others has shown that rapid synthesis of neurosteroids acts to increase inhibition in response to anxiety-inducing stimuli. Our recent work has shown that neurosteroids mediate an induced increase in inhibition in the auditory midbrain area. A surprising aspect of that study was that neurosteroids also appear to mediate ongoing levels of inhibition. This now allows us to use the many inhibitory interactions in the auditory pathway as potential models for studying the role of neurosteroid modulation of GABA inhibition in normal brain function. This is important because a number of medical treaments have the side effect of changing the synthesis of neurosteroids. We will also use an auditory system model of neurotrauma to examine the role of neurosteroids in increasing inhibition (to counter a potentially lethal increase in excitability). The work will involve electophysiological functional measurements and the development of highly sensitivity analytical protocols using an electrospray mass spectrometer for direct measurement of neurosteroids in submicrogram samples of brain tissue.Read moreRead less
Molecular And Cellular Changes Following A Cortical Injury: What Role Do They Play In Regeneration?
Funder
National Health and Medical Research Council
Funding Amount
$499,625.00
Summary
Damage to the visual areas of the brain is common after, for example stroke, neurotrauma or hypoxia. The injury often manifests in the form of a scar caused by a specific type of brain cell (astrocyte). This scar acts as a barrier to the cells which transmit information (neurones), preventing re-establishment of connectivity, thus functional recovery. We will see if we can reduce this scar and enhance re-connectivity after injury by blocking some of the molecules that brain cells express.
Secretion Of Alpha-synuclein: A Diagnostic Marker For Parkinsons Disease And A Clue To Its (patho)physiology
Funder
National Health and Medical Research Council
Funding Amount
$634,051.00
Summary
We have found that a protein, alpha-synuclein is low in people with Parkinson's Disease. We wish to see if this can be used as a diagnostic test for the condition. Alpha-Synuclein is thought to be important in causing Parkinson's Disease. We suspect that by finding out why less of this protein enters the blood stream in Parkinson's Disease, we may discover clues as to how alpha-synuclein causes problems in this condition.
Gene-environment Interactions And Experience-dependent Plasticity In The Healthy And Diseased Cerebral Cortex
Funder
National Health and Medical Research Council
Funding Amount
$249,250.00
Summary
Huntington's disease (HD) is a devastating illness in which movement disorders (including chorea) and mental problems progress for 10-20 years after onset, and inevitably lead to death. HD is caused by an expansion in a repeating segment of DNA in a single gene and is inherited by 50% of the offspring of sufferers. Despite this strong genetic factor, we have recent evidence from a mouse model, in which the human HD gene mutation has been inserted into the mouse genome, supporting a role for envi ....Huntington's disease (HD) is a devastating illness in which movement disorders (including chorea) and mental problems progress for 10-20 years after onset, and inevitably lead to death. HD is caused by an expansion in a repeating segment of DNA in a single gene and is inherited by 50% of the offspring of sufferers. Despite this strong genetic factor, we have recent evidence from a mouse model, in which the human HD gene mutation has been inserted into the mouse genome, supporting a role for environmental factors in disease onset and progression. Following on from our work showing that environmental enrichment delays disease and progression in this mouse model of HD, we are using experimental manipulations of the environment to examine effects on brain degeneration and behaviour. This project aims to investigate gene-environment interactions in HD, focusing on dysfunction of neurons in the cerebral cortex. The combination of behavioural, physiological, anatomical and molecular analysis of HD mice will bring us closer to a comprehensive understanding of HD. This will have implications for the development of new therapies for HD. Our environmental enrichment paradigm may also lead to development of occupational therapy strategies for HD and other neurological disorders. There are at least ten other fatal brain disorders which are caused by the same DNA repeat expansion in other genes. New insights into HD will therefore have implications for the understanding and development of therapeutics for these other DNA repeat expansion brain diseases. Furthermore, another devastating brain disorder which, like HD, involves abnormal protein interactions and dysfunction of the cortex, is Alzheimer's disease. Understanding HD may therefore also have implications for our understanding of Alzheimer's disease. Additionally, analysing control mice in this project will provide new information on mechanisms of plasticity in the normal cortex, which may underlie learning and memory.Read moreRead less
Investigating The Pathogenic Mechanism Of Mutations In IQSEC2 Causing Non-syndromic Intellectual Disability.
Funder
National Health and Medical Research Council
Funding Amount
$449,016.00
Summary
Intellectual disability is frequent in the population, as many as 1 in every 50 people in the world affected. Mutations in IQSEC2, an X-chromosome gene, cause intellectual disability. We will screen 1000 families with this disability for mutations in IQSEC2, building the picture of disease symptoms, contributing to informed genetic counselling. We will investigate functional impacts of these mutations in neuronal cultures, increasing our understanding of the causes of intellectual disability.
Does Pregnancy Cause Morphological Changes In Central As Well As Peripheral Nerve Pathways That Control Blood Pressure?
Funder
National Health and Medical Research Council
Funding Amount
$382,538.00
Summary
Pregnancy changes blood pressure but the mechanism is unknown. We will use state-of-the-art anatomical methods to define how pregnancy alters nerves controlling blood pressure. We will identify changes in the information the nerve cells receive, in their shape and in the way they communicate with other blood pressure-controlling nerve cells. This information will help to develop new ways to prevent and treat pre-eclampsia, a major cause of death and disability for mothers and their newborns.
High Field Magnetic Resonance Evaluation Of Cerebral And Brainstem Dysfunction In Obstructive Sleep Apnea.
Funder
National Health and Medical Research Council
Funding Amount
$335,175.00
Summary
BACKGROUND: Obstructive Sleep Apnea (OSA) is a condition where repetitive obstruction of the upper airway occurs during sleep. This occurs in susceptible patients when the muscles which normally hold the upper airway open relax with sleep onset. During these interruptions to breathing (apneas) oxygen levels can fall significantly and repetitive awakenings from sleep result. Patients with sleep apnea are often sleepy during the day and experience difficulties with concentration on complex or bori ....BACKGROUND: Obstructive Sleep Apnea (OSA) is a condition where repetitive obstruction of the upper airway occurs during sleep. This occurs in susceptible patients when the muscles which normally hold the upper airway open relax with sleep onset. During these interruptions to breathing (apneas) oxygen levels can fall significantly and repetitive awakenings from sleep result. Patients with sleep apnea are often sleepy during the day and experience difficulties with concentration on complex or boring tasks. Recent improvements in magnetic resonance imaging (MRI) technology allow targeting very small areas of the brain, such as the brainstem, the region of the brain which contols the upper airway muscles. MRI can detect subtle signs of damage to brain cells, and can assess brain activation induced by a task, such as moving the tongue . AIM 1. To identify the presence and patterns of damage to brain cells in patients with OSA by MRI scanning. 2. To examine whether patients with the most severe patterns of injury are also those with the greatest difficulties with sleepiness and concentration. 3. To determine whether these brain abnormalities improve after 6 months of treatment of OSA. 4. To assess activity of the brainstem in wakefulness in OSA patients and compare this to the activity in subjects without OSA. SIGNIFICANCE: This project will advance our understanding of the causes of obstructive sleep apnea. We anticipate it will provide a new method for investigating injury to brain cells in this disease. It will also provide a new means for investigating the causes of OSA and for evaluating novel therapies aimed at enhancing the activity of upper airway muscles and preventing obstruction during sleep.Read moreRead less