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Principal Investigator: Samuel Matthew Young
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2022
Award: $154,500
Funding agency: National Center for Advancing Translational Sciences
Project Summary/Abstract
Synapses are the fundamental unit of information transfer in the central nervous system (CNS)
and are composed a highly complex molecular machinery that tightly regulates synaptic
transmission and neuronal circuit output. A multitude of combinations of synaptic proteins and
their isoforms creates synapses with distinct functional properties to enable the broad diversity of
information encoding by neuronal circuits. Human mutations in synaptic proteins result in synaptic
dysfunction which causes neurological disorders such as schizophrenia, epilepsy, ataxia, autism,
and intellectual disability. Currently, 1.5 billion people worldwide suffer from a CNS disorder,
however there are limited therapeutic options. Therefore, elucidating the molecular mechanisms
that control synaptic function are fundamental to developing novel therapeutics for CNS disorders.
The α2δ proteins (α2δ 1-4) are extracellular proteins initially identified as auxiliary subunits of
voltage-gated Ca2+ (CaV) channel complexes and they are drug targets. However, multiple roles
have been described for the α2δ isoforms in independently regulating synaptic function and CaV
channel complexes. Human mutations specific to each α2δ isoform are correlated to distinct brain
disorders. Despite being highly expressed throughout the CNS and the clear linkage between
human mutations in α2δ2 and α2δ3 and CNS disorders, very little is known about the roles of
α2δ2 and α2δ3 in regulating synaptic function. In mammals, the globular bushy cells (GBCs) in
the auditory brainstem highly express both α2δ2 and α2δ3. The GBC axon gives rise to the calyx
of Held, a glutamatergic presynaptic terminal which is the sole input to drive action-potential (AP)
spiking and utilizes rapid, temporally precise AP signaling to encode auditory information. The
calyx is an exceptional model for gaining mechanistic insights into the presynaptic regulation of
synaptic function and neuronal circuit output Therefore our goal is to establish how presynaptic
α2δ2 and α2δ3 regulate synaptic function and neuronal circuit output. We will use novel
transgenic mouse models and viral vectors to manipulate the α2δ2 and α2δ3 at the calyx during
different developmental stages and analyze how their loss impact synaptic transmission and
neuronal circuit output.. Ultimately, our findings will provide fundamental insights into how
information is encoded by the CNS and will facilitate the development of treatments for a wide
range of neurological disorders due to α2δ2 and α2δ3 mutations. Finally, our novel animal models
will be valuable reagents to the Illuminating the Druggable Genome (IDG) program
Terms: <Action Potentials><Adhesions><Animal Model><Animal Models and Related Studies><Ataxia><Ataxy><Auditory><Autism><Autistic Disorder><Axon><Axon Terminals><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><Brain Stem><Brainstem><CNS Diseases><CNS Nervous System><CNS disorder><CRE Recombinase><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Central Nervous System Diseases><Central Nervous System Disorders><Complex><Coordination Impairment><Development><Drug Targeting><Drugs><Dysfunction><Dyssynergia><Early Infantile Autism><Electron Microscopy><Encephalon><Encephalon Diseases><Enterobacteria phage P1 Cre recombinase><Epilepsy><Epileptic Seizures><Epileptics><Evoked Potentials><Extracellular Protein><Frequencies><Functional disorder><Genetic Alteration><Genetic Change><Genetic defect><Genome><Glutamates><Goals><Human><Individual><Infantile Autism><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Ions><Isoforms><KO mice><Kanner's Syndrome><Knock-out Mice><Knockout Mice><Knowledge><L-Glutamate><Mammalia><Mammals><Measures><Medication><Metals><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><Nervous System Diseases><Neural Transmission><Neuraxis><Neurologic Disorders><Neurological Disorders><Null Mouse><Output><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Physiopathology><Presynaptic Nerve Endings><Presynaptic Terminals><Property><Protein Isoforms><Proteins><Reagent><Regulation><Role><Schizophrenia><Schizophrenic Disorders><Seizure Disorder><Signal Transduction><Signal Transduction Systems><Signaling><Site><Slice><Spike Potential><Synapses><Synaptic><Synaptic Boutons><Synaptic Terminals><Synaptic Transmission><Synaptic Vesicles><Therapeutic><Transgenic Mice><Viral Vector><Von Willebrand Factor A Domain><Work><autism spectrum disorder><autistic spectrum disorder><bacteriophage P1 recombinase Cre><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><conditional knock-out><conditional knockout><dementia praecox><develop therapy><developmental><drug/agent><epilepsia><epileptiform><epileptogenic><fully-deleted adenoviral vector><fully-deleted adenovirus vector><genome mutation><glutamatergic><gutless adenoviral vector><gutless adenovirus vector><hdAd><helper-dependent adenoviral vector><helper-dependent adenovirus vector><insight><intellectual and developmental disability><intervention development><model of animal><model organism><mouse model><murine model><nervous system disorder><neurological disease><neuronal circuit><neuronal circuitry><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><patch clamp><pathophysiology><postsynaptic><presynaptic><programs><protein protein interaction><schizophrenic><social role><synapse><synapse function><synaptic function><therapy development><trafficking><treatment development><vesicle release><vesicular release><voltage>