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Principal Investigator: Samuel Matthew Young
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2023
Award: $370,077
Funding agency: National Institute of Neurological Disorders and Stroke
The diversity of information encoding by neuronal circuits is regulated by the magnitude and
location of Ca2+ entry though voltage-gated Ca2+ channels (CaV). In the mammalian central
nervous system, the CaV2.1 channel is the critical subtype for CNS function since it is the most
efficient CaV2 subtype at triggering synaptic vesicle (SV) release. At the majority of synapses,
CaV2.1 is present at higher levels and in closest proximity to SVs. During development synapses
become progressively more dependent on CaV2.1 due to selective reduction of CaV2.2 and
CaV2.3. Neurons that signal with rapid and temporally precise action-potentials use Cav2.1
exclusive synapses that have fast SV release kinetics. Additionally, CaV2.1 is the dominant CaV2
isoform associated with human CaV2 channelopathies that manifest in migraine, epilepsy, and
ataxia. Consistent with these findings, dysregulation of SV release is a cause of these and several
other neurological disorders.
Despite the importance of CaV2.1 in CNS function, we know little about the molecular mechanisms
that regulate these CaV2.1 functions at the synapse. The calyx of Held, a glutamatergic
presynaptic terminal in the auditory brainstem utilizes rapid and temporally precise action potential
signaling for encoding information. The calyx undergoes a developmental change from having
multiple CaV2 subtypes to CaV2.1 exclusively. Since it is the sole input to drive post-synaptic
action potential spiking and due to the ability to directly measure presynaptic Ca2+ currents and
correlate them to SV release rate, the calyx is an exceptional model for gaining mechanistic
insights into the presynaptic regulation of SV release and neuronal circuit output. We will use
transgenic mouse models and novel viral vectors to manipulate CaV2 subtypes at the calyx during
different developmental stages. With these tools and proposed experiments, we will determine
how the CaV2 α1 subunit regulates CaV2 subtype levels, organization and proximity to SVs thereby
controlling synaptic transmission and neuronal circuit output. Given the importance of CaV2
channels in regulating synaptic transmission, as well as the pathological consequences of
aberrant SV release, we envision that our findings will provide fundamental insights into how
information is encoded by the nervous system, facilitating the development of treatments for a
wide range of neurological and neuropsychiatric disorders.
Terms: <Action Potentials><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><Ataxia><Ataxy><Auditory><Axon Terminals><Brain Stem><Brainstem><CNS Nervous System><Cav2.1><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Coordination Impairment><Data><Development><Dyssynergia><Electron Microscopy><Electrophysiology><Electrophysiology (science)><Epilepsy><Epileptic Seizures><Epileptics><Gene Transcription><Genetic Transcription><Glutamates><Goals><Human><Hybrids><Impairment><Intracellular Communication and Signaling><Isoforms><KO mice><Kinetics><Knock-out Mice><Knockout Mice><Knowledge><L-Glutamate><Location><Maps><Measures><Mediating><Migraine><Migraine Headache><Modeling><Modern Man><Molecular><Nerve Impulse Transmission><Nerve Transmission><Nervous System><Nervous System Diseases><Nervous System Physiology><Neural Transmission><Neuraxis><Neurologic Body System><Neurologic Disorders><Neurologic Organ System><Neurologic function><Neurological Disorders><Neurological function><Neuronal Transmission><Neurophysiology / Electrophysiology><Null Mouse><Output><P-Q type VDCC><P-Q type voltage-dependent calcium channel><Pathologic><Presynaptic Nerve Endings><Presynaptic Terminals><Protein Isoforms><Proteins><Publishing><RNA Expression><Regulation><Role><Seizure Disorder><Signal Transduction><Signal Transduction Systems><Signaling><Spike Potential><Synapses><Synaptic><Synaptic Boutons><Synaptic Terminals><Synaptic Transmission><Synaptic Vesicles><Transcription><Transgenic Mice><Variant><Variation><Viral Vector><axon signaling><axon-glial signaling><axonal signaling><biological signal transduction><conditional knock-out><conditional knockout><develop therapy><developmental><electrophysiological><epilepsia><epileptogenic><experiment><experimental research><experimental study><experiments><fully-deleted adenoviral vector><fully-deleted adenovirus vector><glia signaling><glial signaling><glutamatergic><gutless adenoviral vector><gutless adenovirus vector><hdAd><helper-dependent adenoviral vector><helper-dependent adenovirus vector><insight><intervention development><model-based simulation><models and simulation><mouse model><murine model><mutant><nerve signaling><nervous system disorder><nervous system function><neural signaling><neurological disease><neuronal circuit><neuronal circuitry><neuronal signaling><neuropsychiatric disease><neuropsychiatric disorder><neurotransmission><neurotransmitter release><novel><omega-agatoxin-IVA-sensitive VDCC><patch clamp><postsynaptic><preference><presynaptic><protein protein interaction><social role><synapse><therapy development><tool><trafficking><treatment development><vesicle release><vesicular release><voltage>