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Transposon-mediated genetic manipulation of OPCs to study their role in synapse formation

Award Number: R21NS142499
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/17/2026
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Transposon-mediated genetic manipulation of OPCs to study their role in synapse formation - PROJECT SUMMARY Oligodendrocyte precursor cells (OPCs) are best known as precursor cells that generate myelinating oligodendrocytes. In demyelinating disorders such as multiple sclerosis, OPCs are an important source of remyelinating cells. OPCs exist abundantly not only during development when myelinating cells are generated but also in the mature brain in the gray matter as well as white matter. This suggests that OPCs may be involved in cellular functions other than generating myelinating oligodendrocytes. Unlike other non-neuronal cell types, they receive synapses from neurons and depolarize upon stimulation. While past studies have focused on the role of neuron-to- OPC synapses in activity-dependent myelin plasticity, emerging evidence suggests that OPCs play an active role in the neural network, possibly through a mechanism that is independent of myelin. A fundamental question that has not been resolved is how OPCs modulate neuronal network function. Accumulating reports that many of the synaptic proteins previously considered to be unique to neurons are also expressed by OPCs and supports their role in synapse formation or reorganization. As a first step toward elucidating the role of OPCs in neuronal synapses, this project will develop improved techniques and test the hypothesis that OPCs in an activity-dependent manner dynamically modulate nearby neuron-neuron synapses. This will be examined after chemogenetic OPC activation (Aim 1) and in which the gene encoding the synaptic organizer protein C1QL1 is selectively deleted from OPCs (Aim 2). A current challenge in studying neuron-OPC synapses is an inability to quantify them free of confounding signals from nearby neuron-neuron synapses. To solve this problem, while simultaneously monitoring neuron-neuron synapses, we will develop a transposon-mediated conditional in utero electroporation approach optimized to deliver nanobodies that specifically mark excitatory and inhibitory postsynaptic proteins in OPCs. The outcome of the proposed study will likely lead to novel principles regarding the role of OPCs in regulating neuronal excitation or inhibition and have profound impact on the regulatory mechanism and development of therapeutic strategies to ameliorate pathological conditions of altered excitation/inhibition imbalance such as epilepsy, schizophrenia, and autism spectrum disorders.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $471,861 )
2026	2026	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/16/2026	NEW	$471,861
														Subtotal = $471,861

Grand Total All Awards = $471,861

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Transposon-mediated genetic manipulation of OPCs to study their role in synapse formation

Award Number: R21NS142499

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/17/2026

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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