Lee, Hanmi
(2007)
ROLE OF GABA/GLYCINE DEPOLARIZATION AND HYPERPOLARIZATION IN NEONATAL CIRCUIT DEVELOPMENT.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
During development, GABA/glycinergic responses switch from depolarizing to hyperpolarizing due to the gradual decrease in chloride equilibrium potential (ECl) to a more negative value than the resting membrane potential. Depolarizing GABA/glycinergic responses and the developmental switch to hyperpolarization are believed to play a key role in neuronal circuit development, yet a clear demonstration of how and to what degree they are important has not been investigated. In my dissertation studies, I investigated the functional significance of the developmental switch to hyperpolarizing GABA/glycinergic responses in circuit development. To this end, I compared synaptic strength in a brain slice preparation containing the intact topographic pathway of GABA/glycinergic projections from the Medial Nucleus of Trapezoid Body (MNTB) to the lateral superior olive (LSO) between wild type (WT) and KCC2-knockdown (KD) mice. In KCC2-KD mice, the developmental switch to GABA/glycinergic hyperpolarization was prevented due to reduced expression of the potassium chloride co-transporter 2 (KCC2) (KCC2-KD mice). I found that the GABA/glycinergic MNTB to LSO synapses in KCC2-KD mice undergo normal refinement through strengthening and elimination during development. Furthermore, the glutamatergic cochlear nucleus (CN) inputs to LSO neurons maintained their normal strength even when depolarizing MNTB synaptic inputs were strengthened, resulting in an abnormally high amount of depolarization. Based on these results, I concluded that the hyperpolarizing switch of GABA/glycinergic responses is not a necessary condition for the refinement of inhibitory synapses during development. Furthermore, homeostatic regulation of excitability in LSO neurons seemed to be impaired, due to the normal strengthening of depolarizing MNTB synapses together with the unaltered CN synaptic strength in KCC2-KD mice. In addition, my results suggest that GABA/glycinergic synapses can regulate their synaptic strength independently of ECl, emphasizing the importance of chloride homeostasis when investigating the strength of inhibition.However, the strength of the CN inputs to the MNTB, the calyx of Held, was reduced in MNTB neurons in KCC2-KD mice at hearing onset, suggesting that the developmental switch to hyperpolarizing GABA/glycine responses is necessary to maintain the normal strength of the calyx of Held synapse. I discuss possible mechanisms of the reduced strength of calyx of Held synapses in the absence of hyperpolarizing GABA/glycinergic responses. Finally, in immature cortical neuronal cells in vitro, I demonstrated that KCC2 overexpression is sufficient to terminate the GABAergic excitatory period earlier than normal development. Based on these results, I generated KCC2OVER mice in which KCC2 can be overexpressed in a temporally regulated, neuronal-specific manner (Appendix) in vivo. Overexpression of KCC2 both in vitro and in vivo will help us to understand the role of excitatory (or depolarizing) GABA and glycine responses in neuronal circuit development.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
17 July 2007 |
| Date Type: |
Completion |
| Defense Date: |
7 May 2007 |
| Approval Date: |
17 July 2007 |
| Submission Date: |
6 July 2007 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
AUDITORY; DEVELOPMENT; GABA/GLYCINE; INHIBITION; KCC2 |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-07062007-114319/, etd-07062007-114319 |
| Date Deposited: |
10 Nov 2011 19:50 |
| Last Modified: |
15 Nov 2016 13:45 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/8281 |
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