Abstract
The tyrosine kinase Fyn plays an important role in synaptic plasticity, learning, and memory. Here we report that Fyn is activated in response to 15 min D1 receptor (D1R) but not D2 receptor (D2R) stimulation specifically in the dorsomedial striatum (DMS) of mice but not in the other substriatal regions, the dorsolateral striatum (DLS), and the nucleus accumbens (NAc). Once activated Fyn phosphorylates its substrate GluN2B, and we show that GluN2B is phosphorylated only in the DMS but not in the other striatal regions. Striatal neurons are divided into D1R expressing medium spiny neurons (MSNs) and D2R expressing MSNs. Thus, to explore the cell-type specificity of this signaling pathway in the DMS, we developed a Cre-dependent Flip Excision (FLEX) approach to knockdown Fyn in D1R MSNs or D2R MSNs, and proved that the D1R-dependent Fyn activation is localized to DMS D1R MSNs. Importantly, we provide evidence to suggest that the differential association of Fyn and GluN2B with the scaffolding RACK1 is due to the differential localization of Fyn in lipid rafts.Our data further suggest that the differential cholesterol content in the three striatal regions may determine the region specificity of this signaling pathway. Together, our data show that the D1R-dependent Fyn/GluN2B pathway is selectively activated in D1R expressing MSNs in the DMS, and that the brain region specificity of pathway depends on the molecular and cellular compartmentalization of Fyn and GluN2B.
Highlights
Fyn kinase belongs to the Src family of protein tyrosine kinases (PTKs) (Resh, 1998)
To differentiate between Fyn expressed in D1 receptor (D1R) vs. D2 receptor (D2R) medium spiny neurons (MSNs), we developed a method in which short hairpin RNA that targets a specific gene is expressed only in the presence of Cre-recombinase (Cre)
We present data to suggest that the D1R/Fyn/GluN2B signaling pathway is localized to a specific subregion of the striatum, the dorsomedial striatum (DMS), and that within the DMS the signaling cascade is localized to D1R-expressing MSNs
Summary
Fyn kinase belongs to the Src family of protein tyrosine kinases (PTKs) (Resh, 1998). Fyn is highly expressed throughout the developing and adult brain (Umemori et al, 1992; Yagi et al, 1993). Fyn plays an important role in excitatory and inhibitory synaptic transmission (Ohnishi et al, 2011; Trepanier et al, 2012; Chattopadhyaya et al, 2013; Hildebrand et al, 2016), synaptic plasticity learning and memory (Grant et al, 1992; Kojima et al, 1997; Salter and Kalia, 2004). Fyn is composed of regulatory and catalytic domains. The regulatory domain consists of a short unique region at the N-terminus that contains myristoylation and palmitoylation sites
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