The activity and plasticity of dendritic spines and synapses underlie normal cognitive processes, such as learning and memory and are the basis for the complex circuitry found in the brain. Dendritic spines, which are actin-rich protrusions that emanate from the dendrite shaft, comprise most postsynaptic terminals of excitatory synapses. Not surprisingly, abnormalities in dendritic spines are associated with a number of neurological disorders, including Fragile-X syndrome, Down's syndrome, Alzheimer's disease, autism, schizophrenia, and epilepsy. Despite the importance of spines and synapses in the central nervous system, the molecular mechanisms that regulate the activity and plasticity of these structures are not well understood largely because of the current lack of available technologies for probing these structures at single spine/synapse levels. Furthermore, the capability to study synaptic activity and plasticity in individual spines and synapses would provide significant insight into the function and molecular mechanisms that regulate these structures. We are developing novel neuron-glia co-culture microfluidic devices with integrated graphene sensors and electrodes and combining them with scanning photocurrent microscopy to detect and stimulate spine plasticity at sub- synaptic resolution (Specific Aim I). We will use this technology to record electrical properties at individual dendritic spines and synapses and to examine the effects of different electrical stimuli on these structures. Since reorganization of te actin cytoskeleton is thought to underlie the activity, plasticity, and function of dendritic spine and synapses, we will explore the role of actin-binding protein VASP in regulating synaptic activity and plasticity (Specific Aim II). We will alter the expression of VASP and determine the effect on the electrical properties of individual dendritic spines and synapses with the graphene probes. Moreover, we will determine the contribution of this protein to synaptic plasticity. The development of the proposed microfluidic platforms will be of great interest and benefit to neurobiologists by providing a powerful technology for investigating the mechanisms that underlie the electrical activity and plasticity of dendritic spines and synapses at a single synaps level.

Public Health Relevance

Abnormalities in the number, size, and morphology of dendritic spines and synapses are associated with many neurological and psychiatric disorders, including Alzheimer's disease, autism, schizophrenia, epilepsy, and intellectual disorders. We are developing microfluidic devices with integrated graphene sensors and electrodes to detect and stimulate synaptic plasticity with high spatiotemporal resolution and sensitivity. These devices will be used to investigate spine remodeling and its underlying mechanisms, which will provide a better understanding of the key molecules that regulate this process and could lead to new therapeutic approaches for treating these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS095323-01
Application #
9025171
Study Section
Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section (BNVT)
Program Officer
Stewart, Randall R
Project Start
2016-04-01
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
965717143
City
Nashville
State
TN
Country
United States
Zip Code
37240
Zhang, Yuchen; Dodson, Kirsten H; Fischer, Rachel et al. (2016) Probing electrical signals in the retina via graphene-integrated microfluidic platforms. Nanoscale 8:19043-19049