Activity of nAChRs containing alpha9 subunits modulates synapse stabilization via bidirectional signaling programs
Vidya Murthy1, Julián Taranda, A Belén Elgoyhen
1Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA.
Developmental Neurobiology
|October 1, 2009
Summary
Loss of nicotinic acetylcholine receptor (nAChR) alpha9 subunit in mice leads to abnormal inner ear synapse development. This suggests nAChR activity regulates cholinergic synapse formation and function in the cochlea.
Area of Science:
- Neuroscience
- Developmental Biology
- Otolaryngology
Background:
- Cholinergic synapse development in the neuromuscular junction is well-understood.
- Little is known about non-neuromuscular nicotinic synapse development in the cochlea.
- Previous studies showed abnormal presynaptic terminal morphology in mice lacking the nAChR alpha9 subunit.
Purpose of the Study:
- To investigate the molecular mechanisms of inner ear synapse development.
- To understand the role of cholinergic activity in cochlear synaptogenesis.
- To elucidate the function of the nAChR alpha9 subunit in inner ear synapse formation.
Main Methods:
- Utilized nAChR alpha9 subunit null mice to silence cholinergic neurotransmission to hair cells.
- Analyzed presynaptic terminal morphology and protein expression patterns.
- Examined cell adhesion proteins, vesicle recycling machinery, and transcriptional regulators.
- Used mice expressing a point mutant nAChR alpha9 subunit to assess activity-dependent effects.
Main Results:
- Alpha9 null mice exhibited premature, effusive innervation of outer hair cells with delayed cell adhesion protein expression.
- Ectopic innervation collapsed, coinciding with age-related hyperexpression.
- Changes in presynaptic vesicle machinery suggested bidirectional communication between hair cells and presynaptic terminals.
- Loss of nAChR activity decreased CREB binding protein and increased N-Cadherin expression.
- Increased nAChR activity, via a point mutant, drove synaptic hyperinnervation.
Conclusions:
- Hair cell nAChR activity modulates cholinergic synapse development and function in the inner ear.
- Loss of nAChR alpha9 subunit function disrupts normal synaptogenesis, leading to aberrant innervation.
- Bidirectional signaling between hair cells and afferent neurons is influenced by nAChR activity.
- nAChR activity impacts transcriptional regulation involved in synapse formation.
Related Concept Videos
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
01:26Chemical Synapses
Chemical synapses are specialized sites between two neurons or between a neuron and a non-neuronal cell like a muscle, glandular or sensory cell.
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
01:26Chemical Synapses
Chemical synapses are specialized sites between two neurons or between a neuron and a non-neuronal cell like a muscle, glandular or sensory cell.
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
01:20Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
Antiepileptic drugs, such as levetiracetam (Keppra) and brivaracetam (Briviact), have emerged as crucial tools in managing epilepsy. These medications exert their therapeutic effects by targeting the synaptic vesicle protein SV2A, a transmembrane glycoprotein primarily found in the brain.
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
01:45Regulation of Nuclear Protein Sorting
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
01:26Neurochemical Transmission: Sites of Drug Action
Neurochemical transmission, the conduction of electrical impulses between neurons mediated by neurotransmitters, plays a vital role in various physiological processes. Autonomic drugs exert their effects by modulating neurotransmission within the autonomic nervous system. For instance, drugs such as hemicholinium block the precursor uptake necessary for synthesizing acetylcholine, an essential autonomic neurotransmitter. Following synthesis, neurotransmitters are stored in vesicles. Metyrosine...