Lab Website: https://medicine.uiowa.edu/acb/profile/c-andrew-frank

My lab utilizes genetics and electrophysiology to study how synapses maintain stable function.

Homeostasis is a robust form of regulation that allows a system to maintain a constant output despite external perturbations. In the nervous system, homeostasis plays a critical role in regulating neuronal and synaptic activity. Yet the molecular basis of this form of neural plasticity is generally unknown. In the Frank Lab we address this problem using the fruit fly, Drosophila melanogaster. This model allows us to combine electrophysiology with powerful genetic and pharmacological techniques. The overall goal is to define conserved signaling mechanisms that direct synapses to maintain stable properties, like excitation levels.

It is generally believed that molecules controlling the balance of excitation and inhibition within the nervous system influence many neurological diseases. Therefore, understanding synaptic homeostasis is of clinical interest. This area of research could uncover factors with relevance to the cause and progression of disorders such as epilepsy, which reflects a state of poorly controlled neural function.

Synaptic Homeostasis at the Drosophila Neuromuscular Junction: Phenomenology A potent homeostatic regulatory system controls muscle excitation at the Drosophila neuromuscular junction (NMJ). Either genetic deletion of a glutamate receptor subunit (GluRIIA) or pharmacological inhibition of the glutamate receptor (via the drug philanthotoxin-433) drastically decreases postsynaptic sensitivity to neurotransmitter. A homeostatic regulatory system compensates for this deficit by increasing presynaptic glutamate release. The result is that postsynaptic muscle is depolarized at relatively normal levels, despite severely impaired sensitivity to neurotransmitter.

Synaptic Homeostasis: Molecular Mechanism Homeostatic regulation is complex – it must include sensors to detect deviations from normal activity and precise feedback mechanisms to correct those deviations. Through genetic approaches, we uncovered a presynaptic signaling system required for synaptic homeostasis (Figure 2). This system includes at least a few components: Drosophila Eph (receptor tyrosine kinase), Ephexin (Exn, guanine exchange factor), and small Rho-type GTPases, in particular Cdc42. Mutations in genes underlying this signaling system show strong genetic interactions with each other and with mutations in cacophony, which encodes the alpha-1 subunit of the presynaptic CaV2.1-type calcium channel. We postulate that this presynaptic signaling system couples homeostatic retrograde signaling at the synaptic plasma membrane to the modulation of presynaptic calcium channel function and neurotransmitter release. A major effort in the lab is to study how this signaling system fits into a broader context during neurotransmission in general, and during synaptic homeostasis, in particular.

PubMed link

Department/Program Affiliations:
Anatomy and Cell Biology
Genetics
Molecular Medicine
Neuroscience