Ming-fai Fong, 
"The Role of Excitatory Neurotransmission in the Induction of Homeostatic Synaptic Plasticity" 
2014 (Emory University PhD dissertation, co-advised with Peter Wenner)

Abstract

Homeostatic plasticity encompasses a family of compensatory mechanisms that
help maintain stability within neural circuits. Synaptic scaling is a form of homeostatic
plasticity characterized by a coordinated strengthening or weakening of all
synaptic inputs onto a neuron by a common factor as a compensatory response to
altered activity. While synaptic scaling has been widely observed both in vitro and in
vivo, how neural circuits sense altered activity in order to trigger the scaling process
remains unclear. Because prolonged blockade of spiking robustly leads to upward
scaling, a leading hypothesis is that neurons monitor their own firing rates to induce
scaling. However, chronic blockade of AMPA-type glutamate receptors (AMPARs)
also leads to upward scaling, suggesting that reduced excitatory neurotransmission
triggers the scaling process. Spiking and excitatory transmission are highly correlated
at the circuit level, so distinguishing between reductions in firing rate and reductions
in transmission as triggers for scaling presents a unique challenge.
In this dissertation, we systematically investigated the independent roles of reduced
firing rate versus reduced AMPAergic transmission in the induction of homeostatic
synaptic scaling. To test the importance of firing rate in scaling, we used
multi-electrode recordings to continuously monitor spiking activity in cultured cortical
networks during perturbations that trigger upward scaling. While each perturbation
reduced spiking activity to some degree, there was no correlation between the
severity of the reduction in firing rate and the degree of scaling observed. Next, we
independently manipulated firing rate and AMPAergic transmission using two complementary
strategies. First, we blocked AMPARs while restoring normal levels of
spiking using closed-loop optogenetic stimulation. Second, we blocked spiking while
partially restoring AMPAergic transmission using a pharmacological AMPAR modulator.
In both cases, we found that the induction of upward scaling was driven by
reductions in AMPAergic transmission, rather than reductions in firing rate. These
results provide strong evidence that excitatory neurotransmission is the activity signal
sensed by neural circuits in order to trigger homeostatic synaptic scaling. Our
findings highlight the role of synaptic activity in the maintenance of circuit stability
and raise important questions about the role of scaling in learning, development, and
disease.