Maturation of astrocyte glutamate regulation drives the development of cortical inhibition
Abstract: The goal
of this project is to examine the developmental regulation of astrocytic glutamate
uptake in the cortex and determine to what extent dynamic glutamate regulation is an
important feature of cortical development. This is an important question because
homeostatic functions of astrocytes, like glutamate regulation, are actively maturing in
the postnatal cortex. Currently, though, ... read morelittle is known about functional glutamate
regulation in the neonatal cortex. To address this gap in knowledge, I measured the
maturation of functional glutamate uptake in the developing cortex using
electrophysiological recordings of glutamate transporter currents in astrocytes. I found
that glutamate clearance is slow in the neonatal cortex and, furthermore, this slow
glutamate clearance is permissive for extrasynaptic NMDA receptor activation.
Interestingly, we found that the developmental expression of glutamate transporters is
disrupted by neonatal injury in the freeze lesion (FL) model. I hypothesized that
disruptions in glutamate regulation during the injury-induced latent period may underlie
the pathological development that leads to cortical hyperexcitability after FL. I found
no indication that synaptic or phasic glutamate clearance was disrupted, though changes
in ambient glutamate remain to be investigated. The major question arising from this
work is what the functional role of slow glutamate uptake might be in normal cortical
development. I hypothesized that reduced clearance in the neonatal cortex may be
allowing ambient glutamate accumulation. To test this, I used electrophysiological
assessments of tonic NMDA receptor-mediated currents in cortical pyramidal cells and
GABAergic interneurons (INs). I discovered that ambient glutamate tonically activates
NMDA receptors containing GluN2C and/or GluN2D subunits. These receptors are expressed
specifically on cortical INs, therefore specifically INs are tonically depolarized.
Additionally, the tonic current is strongest in cortical INs at P7, at the peak of
GluN2D expression. Finally, blockade of GluN2C/D-containing NMDA receptors with
DQP-1105, from P7-9, causes lasting reductions in GABAergic synapse number and IN
dendritic complexity as well as an increase in cortical hyperexcitability. In summary,
my studies describe a novel mechanism by which developmental regulation of astrocytic
glutamate clearance creates a permissive environment for extrasynaptic and tonic
glutamate signaling, which is necessary for the development of cortical
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Neuroscience.
Advisors: Chris Dulla, and Rob Jackson.
Committee: Yongjie Yang, Dan Cox, and Chinfei Chen.
Keyword: Neurosciences.read less