Identification of Piccolo as a regulator of behavioral plasticity and dopamine transporter internalization

Abstract

Dopamine transporter (DAT) internalization is a mechanism underlying the decreased dopamine reuptake caused by addictive drugs like methamphetamine (METH). We found that Piccolo, a presynaptic scaffolding protein, was overexpressed in the nucleus accumbens (NAc) of the mice repeatedly administrated with METH. Piccolo downexpression by antisense technique augmented METH-induced behavioral sensitization, conditioned reward and synaptic dopamine accumulation in NAc. Expression of Piccolo C 2 A domain attenuated METH-induced inhibition of dopamine uptake in PC12 cells expressing human DAT. Consistent with this, it slowed down the accelerated DAT internalization induced by METH, thus maintaining the presentation of plasmalemmal DAT. In immunostaining and structural modeling Piccolo C 2 A domain displays an unusual feature of sequestering membrane phosphatidylinositol 4,5-bisphosphate, which may underlie its role in modulating DAT internalization. Together, our results indicate that Piccolo upregulation induced by METH represents a homeostatic response in the NAc to excessive dopaminergic transmission. Piccolo C 2 A domain may act as a cytoskeletal regulator for plasmalemmal DAT internalization, which may underlie its contributions in behavioral plasticity.

Functional characterization of the PCLO p.Ser4814Ala variant associated with major depressive disorder reveals cellular but not behavioral differences

“…Previously generated mouse models that manipulated Piccolo levels/function (global knock-down or over-expression of the isolated C2-domain) have shown behavioral phenotypes (Cen et al, 2008;Ibi et al, 2010;Nitta et al, 2010;Mukherjee et al, 2010). This might be due to the fact that these manipulations were more drastic than the knock-in model presented here.…”

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

“…The PCLO gene and a group of semaphorin genes are located in the common deleted interval in patients 2 and 3 ( Figure 2). PCLO encodes the piccolo presynaptic cytomatrix protein, which is involved in monoaminergic neurotransmission 30 and synaptic vesicle exocytosis 31 and has already been associated with major depression disorder. 32 The semaphorins have an important role in the development of the nervous system and in axonal guidance.…”

Trafficking of dopamine transporters in psychostimulant actions

“…In contrast to the effect of wild-type α-synuclein on DAT localization, expression of α-synuclein mutants found in Parkinson’s patients resulted in up-regulation of DAT [56]. Interaction of the amino-terminal tail of DAT with another PDZ-domain containing protein, Piccolo, slowed down DAT endocytosis in both non-neuronal cells and DA neurons [57]. It was suggested that Piccolo reduced clathrin-mediated endocytosis of DAT through its ability to interact with and sequester phospholipid PI(4,5)P2, thus leading to abolished recruitment of several clathrin associated proteins and reduced endocytosis.…”