This proposal is for a K01 Mentored Career Development Award to Promote Faculty Diversity in Biomedical Research for Dr. Nathan A. Smith, a new Assistant Professor of Pediatrics, and Pharmacology and Physiology at Children?s National Health System (CNHS) and George Washington University School of Medicine and Health Sciences (GWSMHS). Dr. Smith is establishing himself as a young investigator in mechanisms of synaptic plasticity with a particular focus on the role of norepinephrine (NE) in astrocytic modulation of synaptic plasticity. This K01 Award will provide Dr. Smith the support necessary to complete the following goals: (1) to acquire patch clamping techniques for slice preparation; (2) to acquire and apply LTD protocols to slice preparation to determine the role of astrocytes in learning and memory; (3) to acquire and learn advance pharmacology techniques in order to specifically block a adrenergic receptors in astrocytes; (4) to develop the skills needed to be an independent investigator through a variety of career development activities and mentorship. To achieve these goals Dr. Smith has assembled a mentoring team comprised of a primary mentor, Dr. Vittorio Gallo, Chief Research Officer at CNHS and a leading authority on glial signaling in health and disease, and two co-mentors: Dr. Stefano Vicini, who has expertise in slice physiology and synaptic plasticity; and Dr. Jason Triplett, who has expertise in sensory circuit development and function and one consultant/collaborator: Dr. Baljit Khakh (UCLA), who is an established investigator and a leader in the field of glial biology and physiology. NE is a major neurotransmitter that modulates a number of brain functions including synaptic plasticity. Recent studies suggest that astrocytes could be involved in NE-induced network modulation. For example, NE has been demonstrated to evoke global Ca2+ transients in cortical astrocytes. Additionally, NE has been shown to enhance astrocytes ability to respond to local synaptic activity in the visual cortex. However, further investigation is needed to elucidate the mechanisms of NE-mediated astrocytic effects on cortical networks and synaptic plasticity. To that end, I will first explore if astrocytes are essential for NE-mediated LTD in the somatosensory cortex using acute cortical slices in our novel GCaMP5G-tdTm/Aldh1l1 mice in Aim 1.
In Aim 2, I will examine NE-induced priming of astrocytes to respond to local synaptic activity. Specifically, I will explore NE-mediated enhancement of astrocytic mGluR3-induced Ca2+ signaling to local synaptic activity in the somatosensory cortex, using both acute cortical slices and in vivo preparations in GCaMP5G-tdTm/Aldh1l1 mice. Finally, in Aim 3, I will test the hypothesis that astrocytes modulate NE-mediated cortical LTD via the release of ATP. Combined, the proposed studies will provide novel insights into the role of astrocytes in synaptic regulation, and thereby in higher information processing through NE-mediated neuromodulation. This research will also form the basis for an R01 application before the end of the K award cycle.
The proposed studies will explore a novel mechanism of astrocytic modulation of synaptic plasticity involving norepinephrine (NE) and ATP. Since NE is known to play an important role in many pathophysiological disorders such as ADHD, depression, epilepsy, and Alzheimer?s disease, these studies may also give new insight into the role that astrocytes play in neurological disease. Illuminating the importance of this novel mechanism of astrocytic modulation of synaptic plasticity may reveal pathways suitable for pharmacological manipulation to treat diseases of the central nervous system.
