Project Details
Description
ABSTRACT
Microglia are brain macrophages derived from yolk-sac progenitors, with classically assigned roles that center
on immune surveillance and response to an injury or a disease state. Recent views, however, have moved
microglia into the landscape of normal brain function, performing activities such as sculpting and refining of
neuronal circuitry in the absence of external stimuli or disease. Thus, understanding the contribution of microglia-
neuron interactions in mental health is an area of active interest. Ionized Ca2+-binding adapter molecule 1 (Iba1
a.k.a. AIF1) is a highly conserved protein expressed in microglia. Iba1 has been used widely as a marker of
microglia, but its contributions to microglial and brain functions remain largely unknown. In preliminary studies of
mice globally deficient for Iba1 function, we have found that this protein is essential for microglial activity,
evidenced by reductions in microglial branching and alterations in the total brain expression of several microglial-
enriched proteins that have roles in synaptic function and behavior. Furthermore, loss of Iba1 reduces
developmental excitatory synaptic strength and synapse numbers but enhances excitation-inhibition ratio
involving the pyramidal neurons of CA1 hippocampus. These developmental deficits correlate with a deficit in
social interaction in adult Iba1-deficient mice. We hypothesize that microglial Iba1 has important synaptic
remodeling functions during postnatal development, which in turn shapes adult behavior. Since, Iba1 is also
expressed in CNS-associated macrophages, circulating monocytes and peripheral tissue macrophages, it is
unclear whether Iba1 function specifically in microglia contributed to the aforementioned effects in synaptic
physiology, gene expression and behavior. To test these ideas, we will take advantage of our unique conditional
Iba1 loss-of-function model to manipulate microglial activity. Our two aims address in turn the neurophysiological
and behavioral consequences of Iba1 loss from microglial cells during a critical developmental window, and to
understand the contributions of Iba1 in the modulation of microglial and synaptic gene expression that underlie
an altered synaptic remodeling and behavior. The proposed work will highlight the importance of synaptic
developmental functions regulated by a microglia-intrinsic protein and further attempt to showcase the impact of
such regulation on behavior. Knowledge gained from this study will advance our understanding of how microglia
contribute to the refinement of neuronal circuitry in a developing brain, and thus may provide a rationale for
therapeutic targeting of microglia, to advance treatment of neurodevelopmental and neuropsychiatric disorders.
Status | Finished |
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Effective start/end date | 12/1/20 → 10/31/23 |
Funding
- NATIONAL INSTITUTE OF MENTAL HEALTH: $243,989.00
- NATIONAL INSTITUTE OF MENTAL HEALTH: $189,000.00
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