GLAST regulates glutamate dynamics and interneuron maturation in the developing cortex
astrocytic glutamate transporters GLAST and GLT-1 are highly expressed in the neocortex
and are critical for regulation of extracellular glutamate concentrations. Glutamate, in
turn, regulates many aspects of postnatal cortical development. However, the relative
contributions and functional roles of GLAST and GLT-1 in the developing postnatal cortex
are not well understood. The ... read moremain goal of this dissertation is to test the hypothesis
that astrocytic glutamate transporters contribute to postnatal cortical circuit
development. To test this hypothesis, I used heterozygous mouse models where there is
50% reduction of GLAST or GLT-1 protein levels. Using astrocyte glutamate transporter
recordings, I show that GLAST is the predominant astrocytic transporter during postnatal
cortical development, while GLT-1 becomes dominant in the mature cortex. This functional
finding confirms previous studies characterizing GLAST and GLT-1 expression and suggests
that GLAST might be critical for the development of cortical circuits. By recording
tonic NMDA currents, we show that decreased GLAST function leads to increased ambient
glutamate in the developing cortex. Previous work done in the lab had shown that
fast-spiking interneurons in the cortex are particularly susceptible to tonic NMDA
activation due to their NMDAR subunit composition. Therefore, I tested whether the
effects of altered tonic glutamate signaling had cell-type specific effects.
Fast-spiking interneurons in the GLAST+/- cortex, but not excitatory pyramidal cells,
have altered action potential firing and intrinsic membrane properties during
development and altered morphology in the mature somatosensory cortex. Additionally,
inhibitory synapse number and interneuron distribution in the cortical layers are
altered in the mature GLAST+/- cortex. Finally, I found that the broad deficits in
inhibitory circuits correlate with altered slice hyperexcitability in the mature
GLAST+/- cortex, suggesting that loss of GLAST function during development leads to loss
of inhibitory control of cortical networks. Since the GLT-1+/- cortex was not
hyperexcitable at this mature stage, the results suggest that the aberrant cortical
network activity observed results from disruptions during development that persist in
the GLAST+/- cortex, rather than from deficits in acute glutamate uptake capacity. Taken
together, the results from my thesis project indicate that GLAST, specifically,
regulates glutamate in the developing neocortex and that its function is critical for
the maturation of inhibitory function in cortical circuits. This main finding is in
contrast with earlier work done in the thesis highlighting a role for GLT-1 in the acute
response to kainic acid-induced seizures.
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Neuroscience.
Advisor: Chris Dulla.
Committee: Michele Jacob, Yongjie Yang, and Janice Naegele.
Keyword: Neurosciences.read less