Fig. 8

Pridopidine enhances cAMP/PKA and TrkB pathway genes in the YAC128 striatum. Shown is a model of gene regulation after treatment with pridopidine in the YAC128 striatum. Dopamine transmission directs the activation of dopamine D1 and D2 receptors (D1R and D2R, respectively) in medium spiny neurons (MSNs) of the striatum. On the WT postsynaptic density of a D1 synapse, D1Rs activate adenylyl cyclase (AC) in MSNs, whereas muscarinic acetylcholine receptor M4 (M4R) inhibits AC activity. In contrast, D2Rs negatively regulate AC in MSNs, while A2ARs are AC agonists. GPR3 activates AC in both D1R and D2R-expressing MSNs, where RGS2 is a target of cAMP signaling. Activation of AC is upstream of cAMP and PKA, which augments NMDAR activity. Dopamine D1 and D2 receptor genes (Drd1 and Drd2) and A2AR gene (Adora2a) are differentially expressed (DE) and downregulated in the YAC128 striatum, but unchanged after pridopidine treatment (black highlighting). Both Rgs2 and Gpr3 are downregulated in YAC128 striatum (Adj. p-val < 0.05) and upregulated after treatment of pridopidine. NMDARs and TrkB receptors are expressed in both D1R and D2R-expression MSNs. NMDAR and TrkB receptors both indirectly activate the transcription factor (TF) CREB in the nucleus via downstream pathways. In turn, CREB activates gene expression of several targets. Genes Arc, Dusp1, Egr1 and Egr2 are downregulated in the YAC128 striatum, but upregulated after pridopidine treatment (Adj. p-val < 0.05). Fos, Fosb, Fosl2, Egr3, and Egr4 are unperturbed in the striatum of YAC128 mice, but expression of these genes is restored after treatment with pridopidine (Adj. p-val < 0.05). Dopamine pathway genes Nr4a1 and Nr4a3 and TF gene Npas4 are downregulated in YAC128 and upregulated after pridopidine treatment (Adj. p-val < 0.05). NPAS4 regulates Gpr3 gene expression