Modulation of Exocytosis and Excitability in Mature Auditory Brainstem Neurons

Document text

Principal Investigator: HENRIQUE Prado VON GERSDORFF
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2022
Award: $375,943
Funding agency: National Institute on Deafness and Other Communication Disorders

PROJECT SUMMARY
The major goal of this Administrative Supplement is to determine the changes in neuronal excitability and
synaptic strength within the mammalian auditory brainstem during Alzheimer’s disease (AD) and during age
related hearing loss (ARHL). We will use well established transgenic mouse lines and strains as experimental
models for AD and ARHL. As proposed in our parent R01 grant, we will study two specialized synapses in the
auditory brainstem: the large calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) and the
small bouton-type glycinergic and glutamatergic synapses of the lateral superior olive (LSO). These synapses
are pivotal for the auditory brainstem circuits that compute high frequency sound source localization. Binaural
hearing constitutes an important mechanism for localizing sound sources in mammalian species. It also provides
a critical means for filtering important auditory inputs from background noise. The inability to distinguish sound
source location or perceive speech in noisy environments are common forms of hearing loss, especially in elderly
individuals. Impaired hearing also contributes for social isolation of individulas who suffer from ARHL, which
reduces their cognitive stimulation, aggravating or even leading to instances of dementia. The long-term goal is
to determine the neuronal excitability and biophysical properties of the MNTB and LSO synapses as animals
experience different stages of AD and ARHL progression. We will perform single cell patch clamp
electrophysiology recordings in mouse brainstem slices from adult and aging mice at different stages of
adulthood and aging in both control and AD models. Our preliminary data show that several fundamental aspects
of brainstem synapses and neuronal excitability are significantly changed already in young adult mice (three
month old) before severe symptoms of AD become clearly manifest. During adulthood and aging, further synaptic
and excitability changes are observed, sometimes in the opposite direction. We thus propose to study the
synaptic strength, short-term synaptic plasticity and neuronal excitability of neurons from the brains of AD and
ARHL mouse models. The first hypothesis is that the intrinsic excitability of LSO and MNTB neurons is
significantly reduced in AD and aging mice models making it harder for excitatory postsynaptic potentials
(EPSPs) to reach spike threshold. The second hypothesis is that the synaptic strength in AD and aging
brainstem synapses changes significantly because of changes in synaptic vesicle release probability and/or
changes in the readily releasable pool size of synaptic vesicles. The results will provide novel insights that reveal
several underlying mechanisms responsible for AD pathology and hearing deficits in young adults and aging
auditory neurons and synapses. The proposed studies will thus greatly stimulate additional activity leading to
significant progress on the fundamental causes of AD dementia and hearing loss in the mammalian brain.

Terms: <1 year of age><1 year old><21+ years old><AD dementia><AD model><AD pathology><Action Potentials><Administrative Supplement><Adult><Adult Human><Age><Aging><Alzheimer><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease dementia><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's pathology><Alzheimers Dementia><Alzheimers disease><Amentia><American><Ammon Horn><Amyloid><Amyloid A4 Protein Precursor><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Protein Precursor><Amyloid Substance><Amyloid beta-Protein><Amyloid beta-Protein Precursor><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Amyloid β-Protein Precursor><Amyloidosis><Animals><Auditory><Auditory Localization><Auditory system><Award><Aβ><Biophysics><Brain><Brain Nervous System><Brain Stem><Brainstem><CBA/CaJ Mouse><Cell Body><Cell Nucleus><Cells><Cochlear nucleus><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Compensation><Cornu Ammonis><Data><Dementia><Deposit><Deposition><Disturbance in cognition><EPSP><Elderly><Electrophysiology><Electrophysiology (science)><Encephalon><Engineering><Environment><Episodic memory><Excitatory Postsynaptic Potentials><Excitatory Synapse><Exocytosis><Experimental Models><Fiber><Financial compensation><Florida><Frequencies><Genetic Alteration><Genetic Change><Genetic defect><Glutamates><Goals><Grant><Hearing><Hearing Loss><Hippocampus><Hippocampus (Brain)><Human><Hypoacuses><Hypoacusis><Impaired cognition><Incidence><Individual><Inhibitory Synapse><L-Glutamate><Lead><Location><London><Medial><Membrane><Memory Deficit><Memory impairment><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Mutation><Nerve Cells><Nerve Unit><Nervous System Diseases><Neural Cell><Neurocyte><Neurologic Disorders><Neurological Disorders><Neurons><Neurophysiology / Electrophysiology><Noise><Nucleus><PSEN1><Parents><Pathology><Pb element><Phase><Physiology><Presbyacusis><Presbycusis><Primary Senile Degenerative Dementia><Probability><Process><Property><Publishing><Resistance><Risk><Rodent><Rodentia><Rodents Mammals><S182 protein><Slice><Social isolation><Sound Localization><Source><Speech><Spike Potential><Symptoms><Synapses><Synaptic><Synaptic Vesicles><Synaptic plasticity><Testing><Transgenic Mice><Work><a beta peptide><abeta><adult youth><adulthood><advanced age><age 1 year><age associated hearing loss><age induced hearing loss><age related decline in hearing><age related hearing deficits><age related hearing impairment><age related hearing loss><aged><aged 1 year><aged brain><aged one year><aged population><ages><aging associated hearing loss><aging brain><aging induced hearing loss><aging population><aging related decline in hearing><aging related hearing deficits><aging related hearing impairment><aging related hearing loss><alzheimer model><amyloid beta><amyloid disease><amyloid pathology><amyloid precursor protein><amyloid-b protein><beta amyloid fibril><binaural clusters><binaural hearing><biophysical characteristics><biophysical characterization><biophysical foundation><biophysical measurement><biophysical parameters><biophysical principles><biophysical properties><biophysical sciences><cognitive dysfunction><cognitive loss><dementia of the Alzheimer type><dysfunctional hearing><elders><electrophysiological><experience><familial AD><familial Alzheimer><familial Alzheimer disease><genome mutation><geriatric><glutamatergic><hearing defect><hearing deficit><hearing difficulty><hearing disability><hearing dysfunction><hearing impairment><heavy metal Pb><heavy metal lead><hippocampal><insight><late life><later life><lateral superior olive><membrane structure><memory dysfunction><mouse model><murine model><nerve cell death><nerve cell loss><nervous system disorder><neurological disease><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal excitability><neuronal loss><normal aging><novel><older adult><older person><one year of age><one year old><overexpress><overexpression><patch clamp><population aging><presenilin 1 protein><presenilin-1><primary degenerative dementia><resistant><senile dementia of the Alzheimer type><senior citizen><soluble amyloid precursor protein><sound><sound frequency><source localization><synapse><synapse function><synaptic function><trapezoid body><vesicle release><vesicular release><young adult><young adulthood>