Genetic variation in the dystrobrevin binding protein 1 (DTNBP1) gene has been linked to cognition and neurological diseases such as schizophrenia and bipolar disorder. Unfortunately, the neuronal function of the encoded product, dysbindin, is poorly understood. Many reports have claimed that dysbindin deficiency leads to defects in synaptic transmission. However, the specific impairments reported have been variable and inconsistent even at the same synapse. I conducted an independent functional characterization of hippocampal synapses in sandy mice, which contain a spontaneous deletion in the DTNBP 1 gene resulting in the loss of expression of dysbindin, the protein that it encodes. I had observed enhanced excitatory basal synaptic transmission at the CA3-CA1 connection of juvenile mice, which has not been reported in the literature. To understand this novel phenomenon in better detail, a series of experiments was performed in hippocampal slices and cultures to functionally dissect the specific molecular constituent underlying this synaptic impairment. Several experiments for pre-synaptic function conducted in slices and cultures measuring paired-pulse responses in slices, and the rate of synaptic vesicle exocytosis and miniature frequency in cultures revealed the absence of alterations in the release of neurotransmitter. However, experimentation of post-synaptic function revealed an enhancement in excitatory current from spontaneous miniature events in cultures and an enhancement in evoked AMPA receptor transmission from CA1 cells in slices. Thus, the enhanced CA3-CA1 basal synaptic transmission was due to a post-synaptic defect originating from an enhancement in CA1 AMPA receptor current. An increase in the ratio of surface/intracellular expression for the GluR2 and GluR3 subunits in hippocampal slices suggested that the enhancement of CA1 AMPA receptor transmission was due to an increase in the number of surface AMPA receptors. Furthermore, the increase in CA1 AMPA receptor transmission was likely to be due to a defect in the re-distribution of AMPA receptors between the surface membrane and intracellular compartments because no changes were observed in the total expression of the GluR2 and GluR3 subunits in sandy mice. The composition of the increased number of surface AMPA receptors appeared subunit specific because neither changes in the ratio of surface/intracellular expression for the GluR1 and GluR4 subunits, nor changes in GluR1S845, which is associated with GluR1 surface expression, were observed in hippocampal preparations. Enhanced single channel conductance in the AMPA receptor did not appear to contribute to the increase of evoked CA1 AMPA receptor transmission. Indeed neither changes in the proportion of AMPA receptors lacking GluR2 subunit, which have a high single channel conductance, nor in the phosphorylation of GluR1S831, which is associated with high single channel conductance, were found. These data favor a model whereby loss of dysbindin likely leads to enhanced recycling of AMPA receptors to the membrane surface from an intracellular compartment. Consistent with this model, CA3-CA1 LTP, a type of synaptic plasticity that is thought to underlie learning and memory and is known to involve AMPA receptor trafficking to the synapse, was enhanced in sandy juvenile mice. Taken together, these results demonstrate that dysbindin expression plays a key role in modulating the sub-cellular distribution of AMPA receptors at the CA3-CA1 synapse which likely influences both basal synaptic transmission and plasticity.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/D8445TT7 |
| Date | January 2011 |
| Creators | Orozco, Ian Jay |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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