α-Synuclein is the major pathological component of synucleinopathies including 
Parkinson's disease and dementia with Lewy bodies. Recent studies have 
demonstrated that α-synuclein also plays important roles in the release of 
synaptic vesicles and synaptic membrane recycling in healthy neurons. However, 
the precise relationship between the pathogenicity and physiological functions 
of α-synuclein remains to be elucidated. To address this issue, we investigated 
the subcellular localization of α-synuclein in normal and pathological 
conditions using primary mouse hippocampal neuronal cultures. While some neurons 
expressed high levels of α-synuclein in presynaptic boutons and cell bodies, 
other neurons either did not or only very weakly expressed the protein. These 
α-synuclein-negative cells were identified as inhibitory neurons by 
immunostaining with specific antibodies against glutamic acid decarboxylase 
(GAD), parvalbumin, and somatostatin. In contrast, α-synuclein-positive synapses 
were colocalized with the excitatory synapse marker vesicular glutamate 
transporter-1. This expression profile of α-synuclein was conserved in the 
hippocampus in vivo. In addition, we found that while presynaptic α-synuclein 
colocalizes with synapsin, a marker of presynaptic vesicles, it is not essential 
for activity-dependent membrane recycling induced by high potassium treatment. 
Exogenous supply of preformed fibrils generated by recombinant α-synuclein was 
shown to promote the formation of Lewy body (LB) -like intracellular aggregates 
involving endogenous α-synuclein. GAD-positive neurons did not form LB-like 
aggregates following treatment with preformed fibrils, however, exogenous 
expression of human α-synuclein allowed intracellular aggregate formation in 
these cells. These results suggest the presence of a different mechanism for 
regulation of the expression of α-synuclein between excitatory and inhibitory 
neurons. Furthermore, α-synuclein expression levels may determine the efficiency 
of intracellular aggregate formation in different neuronal subtypes.