The function of neuroligin-2 in neuronal development and neuropsychiatric disorders
Open Access
- Author:
- Sun, Chicheng
- Graduate Program:
- Cell and Developmental Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 19, 2013
- Committee Members:
- Gong Chen, Dissertation Advisor/Co-Advisor
Douglas Cavener, Committee Chair/Co-Chair
Zhi Chun Lai, Committee Member
Richard W Ordway, Committee Member
Rick Owen Gilmore, Committee Member - Keywords:
- Neuroligin
Synapse
GABA
Schizophrenia
KCC2 - Abstract:
- Synapse is the functional unit for brain functions. Neuroligins are a family of cell adhesion molecules found at the postsynaptic sites of both excitatory glutamatergic and inhibitory GABAergic synapses. The trans-synaptic interactions between neuroligins and their presynaptic receptor neurexins regulate synapse formation and function. First, I investigated the functional defects of novel neuroligin-2 mutations linked to schizophrenia. In a cohort of 584 schizophrenia patients, we identified novel neuroligin-2 missense point mutations. Among them, I identified R215H as a loss-of-function mutation applying a heterologous GABAergic synapse induction assay. The R215H mutant was defective in mediating cell adhesion and in promoting GABAergic synapse formation. Mechanistically, the R215H mutant showed significantly reduced cell surface expression possibly due to incomplete glycosylation. My work suggests that defect in GABAergic synapse formation may be a potential risk factor for schizophrenia. In the second part of my thesis, I reported a novel function of neuroligin-2 in regulating GABA functional switch from excitation to inhibition through KCC2. KCC2 expression was significantly reduced after knockdown of neuroligin-2 by shRNA-mediated RNA interference. Knockdown of neuroligin-2 abolished GABA functional switch in developing neurons and reversed GABA action to excitatory in mature neurons. Overexpression of shRNA proof neuroligin-2 rescued both decreased KCC2 expression and delayed GABA functional switch induced by shRNAs. Using gramicidin-perforated patch clamp recordings, I further demonstrated that neuroligin-2 expression level directly regulates GABA equilibrium potential. In addition, I showed that KCC2 overexpression rescued glutamatergic synapse loss induced by knockdown of neuroligin-2, suggesting that neuroligin-2 regulates glutamatergic synapses through KCC2. In summary, my findings uncovered a new function of neuroligin-2 in regulating GABA functional switch and glutamatergic synapse formation. Therefore, in addition to its conventional role of cell adhesion at GABAergic synapses, neuroligin-2 may serve as a master regulator in balancing excitation and inhibition in the brain. Dysfunctions of neuroligin-2 may cause excitation/inhibition imbalance and contribute to the etiology of neuropsychiatric disorders, as indicated by the case of neuroligin-2 R215H mutant in schizophrenia.