Appropriate synapse formation and maturation are critical processes contributing to brain development. We now know that synaptic connections between neurons are extensively affected by astrocytes. Astrocytes, by virtue of their elaborate synapse-associated processes, in conjunction with secreted molecules, promote synapse formation, enhance synapse maturation, and regulate synapse elimination. Alterations in astrocyte morphology have repeatedly been shown to lessen the number and/or strength of excitatory synapses. However, not all astrocytes are associated with synapses. A single grey-matter astrocyte can encompass tens of thousands of synapses within its complex, highly branched arbor. In contrast, less-branched white-matter astrocytes are located in regions of low synapse density. The molecular mechanisms by which astrocyte identity is specified and maintained are largely unknown. In a screen of molecules enriched in developing grey-matter vs. white-matter astrocytes, we identified adrenergic receptors as preferentially enriched in the grey-matter astrocyte population. This suggests that norepinephrine may be an important positive modulator of grey-matter astrocyte maturation. Preliminary evidence in this proposal shows that astrocytes express the beta 1 adrenergic receptors. Stimulation of beta-adrenergic receptors increases astrocyte primary branching in vitro, while depletion of norepinephrine or beta-adrenergic receptors in vivo causes cortical grey-matter astrocytes to exhibit reduced morphologic complexity, along with reduced expression of grey-matter astrocyte markers. This proposal will test the hypothesis that norepinephrine signals through astrocytic beta-adrenergic receptors to increase morphologic complexity, which in turn increases their capacity to support synapse formation and function.
Aim 1 will use global and astrocyte-specific conditional deletion of the beta 1 adrenergic receptor to determine whether beta-adrenergic signaling drives astrocyte morphologic complexity and molecular identity.
Aim 2 will use the same experimental models to identify the impact of beta-adrenergic signaling on the development of cortical excitatory synapses. Data from these aims will elucidate how norepinephrine, a ubiquitous neuromodulator dynamically altered in processes such as arousal and stress, influences the development of grey-matter astrocytes and their ability to promote excitatory synapse development in the cortex.
Grey-matter astrocytes are integral to the processes of synapse formation and maturation during brain development. We observed that norepinephrine (NE) signaling can modulate grey-matter astrocyte development, finding that stimulation of NE signaling promotes branching, while depletion of NE signaling reduces morphologic complexity and alters grey-matter astrocyte markers. This proposal will build off these preliminary data to determine the mechanisms by which NE, a key neuromodulator altered in conditions of arousal and stress, influences grey-matter astrocyte maturation and excitatory synapse formation.
