Synucleins as Modulators of Synaptic Function

To determine the in vivo functional roles of a-Syn, a number of groups have generated knockout mice lacking a-Syn expression (30-33). The results from a-Syn knockout mice indicate that a-Syn is not essential for the development and viability of the mice. The DAergic cell bodies, fibers, and synapses in the a-Syn knockout mice were not different from the wild type mice, indicating that loss of a-Syn function is not associated significant pathologic changes in the neuronal systems.

The first report of an a-Syn knockout mice showed that while the patterns of DA discharge and reuptake were unremarkable, DA terminals in a-Syn knockout mice were able to recover faster from the initial activation of transmitter release (30). These results were interpreted to indicate that a-Syn is a presynaptic, activity-dependent, negative regulator of DAergic neurotransmission. In addition, a-Syn knockout mice show reduced total striatal DA levels and reduced amphetamine-stimulated locomotion. While the bases for these latter phenotypes are not known, the first report of a-Syn knockout mice seems to support the notion that a-Syn is a presynaptic regulator of DA release, synthesis, and storage.

The initial conclusions regarding a-Syn as a presynaptic regulator of DA release appears to be supported by results from other groups that have independently analyzed mice lacking a-Syn expression (34,35). Ultrastructural and physiologic studies of hippocampal neurons from another a-Syn knockout mice revealed that the lack of a-Syn expression was associated with reduction in the reserve pool of synaptic vesicles and impaired synaptic response to high-frequency stimulation (34). Real-time voltametric monitoring of DA release in C57BL6 mice with the natural deletion of a-Syn gene (36) revealed that lack of a-Syn was associated with enhancement in the readily releasable pool (RRP) of DA at the expense of the storage pool (35). The increase in RRP in the a-Syn-null mice was ascribed to increase in the rate of refilling the RRP. However, one study has failed to find significant alterations in synaptic function in a-Syn knockout mice (31).

Modest phenotypes of the a-Syn knockout mice are unlikely due to some functional compensation by either ft- and 7-synuclein. Double knockout mice lacking the expression of either a/ fi-Syn or a/ )-Syn are viable without obvious behavioral or synaptic abnormalities (31,37), confirming the view that the synucleins, in general, are not essential for the viability of the organisms. However, it is currently unknown if these combination knockout mice have more severe alterations in the DAergic neurotransmission.

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