Microglia in models of normal brain development, prenatal immune stress and genetic risk for autism
- Awarded: 2015
- Award Type: Research
- Award #: 346197
Microglia — the brain’s resident immune cells — have many roles in normal brain development that neuroscience is just beginning to ascertain. It has long been known that microglia rapidly transform from a homeostatic to an ‘activated’ state following injury or disease and are recruited to sites of damage. A recent and increasing body of work now indicates that microglia also perform important roles in the normal development of the nervous system. For example, microglia sculpt neuronal circuits by removing under-utilized synapses. Microglia also appear to regulate synaptic maturation and plasticity and can impact behavior.
In this study, Steven McCarroll and Beth Stevens hope to gain an understanding of the trajectory of microglia development and activity in the developing brain, including the diversity of cell states that microglia assume as they interact with developing neuronal circuits and the way in which this normal trajectory is disrupted by genetic and immune perturbations relevant to autism.
They will accomplish this goal with an integrative, multidisciplinary strategy combining diverse experimental approaches, including (i) a transformative approach that the McCarroll laboratory has recently developed for single-cell profiling (‘Drop-Seq’)1; this methodology will be used to transcriptionally profile the physiological states of more than 100,000 individual microglia across brain development; (ii) imaging and immunohistochemistry to relate the discovered molecular changes to brain regions and potential cellular foci; and (iii) use of mouse mutants and models of gestational immune stress to ascertain the consequences and specific mechanisms of autism-relevant genetic and environmental perturbations on the natural course of microglial development.