Developing neural circuits undergo critical periods of refinement to establish precise connectivity. During these critical periods, neuronal activity and programmed cell death (PCD) shape the anatomy and function of neurons (i.e. neuronal plasticity). Dysregulation of plasticity has been identified as a common step in the etiology of neurodevelopmental disorders such as autism and schizophrenia. Neuronal plasticity encompasses axon and dendrite remodeling, synapse formation and elimination, changes in the molecular architecture of pre- and postsynaptic specializations, and adjustments to intrinsic excitability. While much is known about the regulation and action of individual plasticity mechanisms, how different plasticity mechanisms cooperate during neural development is not well understood. Recent evidence indicates that crosstalk between these mechanisms governs their function , and suggests that the interplay of plasticity mechanism depends on neuron type and in vivo circuit context. Here, we propose to study how diverse plasticity mechanisms cooperate across different levels of in vivo neural organization (synapse, neuron and circuit), in different cellular compartments (dendrite and axon), and in response to different triggers (neuronal activity and PCD) to shape the development and function of retinal bipolar cells (BCs), glutamatergic second order neurons of the visual system. Towards this end, we have generated transgenic mouse lines that selectively interfere with synaptic input to or output from BCs, or in which BCs can be removed in a graded manner concurrent with their naturally occurring PCD. To analyze structural and functional plasticity, we have established optical approaches from superresolution microscopy, to confocal reconstructions and 2-photon live imaging and optimized methods for targeted patch-clamp and anatomically aligned multielectrode array (MEA) recordings. Thus, we aim to provide an integrated view how diverse activity- and cell- density-dependent plasticity mechanisms cooperate to guide the development of a specific class of neurons and their integration into precise circuits in vivo.

Public Health Relevance

This proposal aims to provide insight into the mechanisms by which developing neurons adapt to changing cellular interactions (i.e. neuronal plasticity). A better understanding of neuronal plasticity has important clinical ramifications: (i) for the understanding and treatment of retinal diseases that trigger maladaptive forms of plasticity (e.g. Retinitis pigmentosa, age-related macular degeneration), (ii) for the rational design of neuron replacement therapies (e.g. photoreceptor transplantation), and (iii) for insight into neurodevelopmental disorders caused by dysregulations of plasticity.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY023341-01A1
Application #
8631379
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Greenwell, Thomas
Project Start
2014-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$342,000
Indirect Cost
$117,000
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130