Presynaptic inhibitory synapses positioned across axon terminals of sensory neurons critically regulate information flow across sensory circuits, allowing meaningful interactions of an organism with its external environment. Whereas much is known about the functional role of presynaptic inhibitory synapses across sensory circuits; little is known about the mechanisms that regulate the development, maturation and maintenance of these inhibitory synapses. Using the well-characterized dim-light (rod) visual circuit of the mammalian retina we uncovered a synaptic reorganization during assembly of GABAergic presynaptic inhibitory synapses that regulate dim-light retinal output. The current proposal aims to determine the cell-autonomous and non-cell autonomous mechanisms that regulate this developmental plasticity during assembly of inhibitory feedback circuits that regulate the gain of sensory (retinal) signal transfer. Our research will yield fundamental information about: (i) retinal circuit assembly (ii) organization of sensory circuits and mechanisms that regulate sensory feedback, and (iii) principles that regulate receptor plasticity during establishment of inhibitory circuits across the CNS. We will combine murine transgenic approaches with high resolution light microscopy, 3D electron microscopy and electrophysiology to address the following three Aims.
In Aim 1 we will determine if cell-autonomous alterations in chloride transporter expression across developing retinal rod bipolar neurons drive and regulate the timing and/or occurrence of the developmental GABAA receptor reorganization.
Aim 2 will determine the contribution(s) of excitatory and inhibitory neurotransmission onto the retinal rod bipolar neuron in regulating the developmental GABAA receptor plasticity.
Aim 3 will determine the role of early visual experience in regulating GABAA receptor reorganizations and assembly of feedback inhibitory synapses of the dim-light retinal circuit. Our research will reveal the interplay between cell-autonomous mechanisms, synaptic input, network activity and environmental cues during establishment and maturation of feedback inhibitory circuits that regulate sensory output. Our study will also reveal circuit plasticity motifs that can be recruited to ameliorate dysfunction during retinal diseases. Furthermore, our findings will determine the developmental sequence of maturation during assembly of invivo presynaptic inhibitory circuits to compare with exvivo retinal assembly such as when pluripotent stem cells are used for retinogenesis.
The developing nervous system exhibits plasticity during formation of connections (synapses) between neuronal partners; disruption of which can lead to abnormal processing (dysfunction) of the brain. We observe synaptic reorganizations during development of connections in the inner retina and the main goal of this research is to determine the cell-autonomous and non-cell autonomous mechanisms that regulate the timing and occurrence of synaptic reorganizations during retinal circuit assembly. Our research will reveal the mechanisms driving developmental plasticity and circuit organization during establishment of sensory circuits and will determine circuit plasticity motifs that can be accentuated or curtailed as part of repair strategies for retinal degenerative diseases.
