Publication Date

2016-04-11

Availability

Embargoed

Embargo Period

2018-04-11

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biology (Arts and Sciences)

Date of Defense

2016-03-07

First Committee Member

Julia Dallman

Second Committee Member

Athula Wikramanayake

Third Committee Member

Akira Chiba

Fourth Committee Member

Stephan Züchner

Abstract

To generate rhythmic motor behaviors, both single neurons and neural circuits require a balance between excitation and inhibition (E/I balance). Disruption of E/I balance is associated with many neurodevelopmental disorders, such as seizures, autism, startle disease and glycine encephalopathy. E/I balance is maintained at both the cellular and the systems levels, and is influenced by the relative distribution of excitatory and inhibitory synapses. While the spatial and temporal patterns of excitatory and inhibitory synapses strongly associate with E/I balance, it remains unclear how perturbations of E/I balance affect the spatial and temporal patterning of synapses in in vivo neural circuits. To answer this question, we investigated the spatial and temporal patterning of excitatory and inhibitory synapses in developing zebrafish spinal cord (Chapter 2). We hypothsized that excitatory and inhibitory synapses and neuronal processes follow a stable, systems-level spatial pattern on the medial-lateral axis in embryonic and larval spinal cord. Interestingly, this pattern is maintained in the zebrafish glycine transporter 1 mutant despite the presence of perturbation of E/I balance (Chapter 3). This mutant can naturally re-establish the spinal cord E/I balance with development. We found that though the general synapse pattern remains unchanged, subtle alterations of synapse spatial patterns take place at the beginning of the E/I balance re-establishment process. We also investigated how a perturbation of E/I balance impacts the synaptogenesis process. To understand this, we knocked down genes encoding particular subunits of glycine receptors (GlyRs) in zebrafish embryos, and analyzed how such knockdown affects glycinergic synaptogenesis and motor behaviors (Chapter 4). We found that disruption of different GlyR subunits impacts the formation of functional glycinergic synapses in different manners: knocking down the GlyR α1 subunit leads to a reduction of GlyRs while knocking down the βb subunit disrupts the clustering of GlyRs at the post-synapses. In addition, knockdown of either subunit alters the spatial pattern of glycinergic synaptogenesis. In conclusion, we found that E/I balance is associated with the spatial and temporal patterns of synapses at multiple levels. The systems-level pattern is stable and robust, while finer-scale patterns at cellular and dendritic levels are more flexible and likely to alter in response to perturbations of E/I balance.

Keywords

Excitatory and inhibitory synapses; E/I balance; spinal cord; zebrafish; motor behavior; patterning

Available for download on Wednesday, April 11, 2018

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