Physiologic roles of type i interferon responsive microglia in brain development

Active Project Grant Awarded Last action

Award ID
R01MH135137
Recipient
Awarding agency
Obligated
$2,653,458

Award facts

Assistance listing
93.242 Mental Health Research Grants
Completion date 51% complete
Place of performance
San Francisco, CA 94158, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The immune system plays key roles in brain development, but immune challenges in early life can also increase the risk for neurodevelopmental disorders including autism and schizophrenia. Microglia, the dominant immune cells of the brain parenchyma, mediate this brain-immune axis by regulating neural circuit development in response to immune cues. A relatively unexplored function of microglia in early brain development is the engulfment of whole neurons, which may engage distinct phagocytic mechanisms from those used, for example, to remodel synapses. In preliminary experiments, we have identified a molecularly distinct subset of microglia in the early postnatal mouse somatosensory cortex (P5) that is actively engulfing whole neurons. These microglia express a type i interferon (IFN-i) responsive molecular signature and have a unique phagocytic morphology in situ, frequently engulfing several neurons at a time. While these cells are rare in the typically developing cortex, they expand 20-fold in somatosensory cortex in a partial whisker deprivation model that accelerates developmental circuit remodeling. We find that both global and microglial-specific deletion of the IFN-i receptor (IFNAR1) leads to dysmorphic microglial with enlarged phagolysosomes and an accumulation of neurons with double strand DNA breaks, a damage/hyperexcitability marker. Our central hypothesis is that type i interferon- responsive microglia promote somatosensory circuit maturation by eliminating specific neurons in early postnatal development. We will test this hypothesis in three specific aims. In aim 1, we will follow up on preliminary data showing that IFNAR1-deficient juvenile animals have altered numbers of deep layer cortical neuronal subtypes, with an increase in excitatory neuronal density, as well as hyperreactive sensory responses to whisker stimulation. We will further examine these phenotypes in global and microglial-specific IFNAR1 deletion by electrophysiology, behavior, and immunohistochemistry. Aim 2 will expand on our preliminary data showing that exogenous IFN-i (IFN-) is sufficient to expand irms and reduce the number of neurons with dsdna breaks. Using our whisker deprivation and pharmacologic gain of function models, we will probe the sources and targets of IFN-i in the developing brain, and the circuit impact of excess IFN-i signaling. Aim 3 follows up on our data that identifies dsrna sensing via mavs as the potential molecular pattern that amplifies IFN-i responses in these microglia. We will use in vivo conditional deletion and in vitro cocultures to define the sources and cellular targets of dsrna in developing cortex. Our long-term goal is fully define the unexpected implications of microglial engulfment of neurons in cortical development, and more broadly, to define the novel homeostatic role of this innate immune pathway in the developing nervous system. 

Transactions

Action Obligated Date
Amendment $697,884
Amendment $593,114
Amendment $681,230
Original award $681,230

Quick answers

Who received award R01MH135137?

R01MH135137 was awarded to The Regents Of The University Of California. San Francisco by National Institute of Mental Health (National Institutes of Health) on July 1, 2024.

How much is award R01MH135137 worth?

$2,653,458 has been obligated on R01MH135137.

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