The output of a neuron is shaped not only by excitation but also by the magnitude and timing of inhibition mediated by the neurotransmitters, gamma-aminobutyric acid (GABA) and glycine. Circuits become dysfunctional as found in many diseases of the nervous system when excitation is not controlled properly by inhibition. Our understanding of the cellular interactions that assemble and maintain appropriate inhibitory connections lags far behind our knowledge about excitatory circuits. In this project, we propose to significantly advance knowledge of the development and functional maintenance of inhibitory connections that control the release of excitatory neurotransmitters from axons. We will focus on inhibitory synapses on the axon terminals of retinal bipolar cells. These neurons are essential for relaying visual signals from photoreceptors to the retinal ganglion cells. Transmission from these cells is shaped by at least two different types of inhibitory synapses.
In Aim 1, we will genetically label ionotropic GABAA and GABAC receptors that regulate inhibition onto the same axon, but with different kinetics. We will use correlative fluorescence imaging and serial block face scanning electron microscopy to map connectivity patterns of the different synapse types. Using GABA receptor subunit specific conditional knockout mice, we will determine whether mature GABAergic synapses bearing alpha1 GABAA receptor subunits require the presence of alpha3 subunits that are transiently abundant during development.
In Aim 2, we will employ imaging, electrophysiological assays, and mutant mice with perturbed inhibitory transmission to ascertain the role of neurotransmission in establishing the appropriate combination of inhibitory synapse types on bipolar cell axons.
In Aim 3, we will distinguish the pathways that are employed to regulate GABAergic synapses in distinct cell compartments, axon versus dendrite, of bipolar cells. We will use molecular and genetic approaches to alter intracellular chloride flux specifically in these neurons. Our results will significantly advance understanding of the cellular mechanisms that regulate the development and maintenance of presynaptic inhibition across circuits that act in parallel to process sensory signals.
Disruption of neuronal connectivity leads to abnormal processing of signals, developmental disorders, brain dysfunction and disease. The broad goal of this project is to investigate and understand the cellular mechanisms responsible for ensuring the accurate relay of sensory signals from the retina to the brain, through the regulation of neuronal excitation by inhibition.
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