Differential Expression of Liprin-α Family Proteins in the Brain Suggests Functional Diversification

Liprin-alpha proteins are major protein constituents of synapses and are important for the organization of synaptic vesicles and neurotransmitter receptors on their respective sides of the synapse. Although it is becoming apparent that the single liprin-alpha gene in invertebrates is essential for synapse function, it is not known to what extent the four different liprin-alpha homologs (liprin-alpha 1-4) in mammals are involved at synapses. We have designed specific antibodies against each of the four liprin-alpha proteins and investigated their regional and cellular distribution in the brain. Here we show that all four liprin-alpha proteins are present throughout the mature brain but have different regional distributions, which is highlighted by their differential localization in olfactory bulb, hippocampus, and cerebellar cortex. Double-immunofluorescence staining indicates that different liprin-alpha proteins are enriched in different synaptic populations but are also present at nonsynaptic sites. In particular, liprin-alpha 2 is preferentially associated with hippocampal mossy fiber endings in the CA3, whereas synapses in the molecular layers of the CA1 and dentate gyrus double-labeled for liprin-alpha 3. The localization of liprin-alpha 2 and liprin-alpha 3 with excitatory synapses was confirmed in cultured primary hippocampal neurons. Liprin-alpha 4, which poorly co-distributed with presynaptic markers in hippocampus, instead strongly co-localized with VGLUT1 in the cerebellar molecular layer, suggesting its presence in parallel fiber-Purkinje cell synapses. Finally, staining of cultured glial cells indicated that liprin-alpha 1 and liprin-alpha 3 are also associated with astrocytes. We conclude that liprin-alpha family proteins might perform independent and specialized synaptic and nonsynaptic functions in different regions of the brain. J. Comp. Neurol. 519:3040-3060, 2011. (C) 2011 Wiley-Liss, Inc.