Synaptic Plasticity, a Prominent Contributor to the Anxiety in Fragile X Syndrome

Figure 1

Signaling pathways downstream of Group I mGluR stimulation. There are three signaling pathways downstream of mGluR5 affecting translation: the typical PLC cascade reaction, the MEK-ERK-Mnk1, and the PI3K-mTOR pathway. Activation of mTOR is one of the primary triggers for the initiation translation via phosphorylation of 4E-BP and S6K. After stimulation of mGluR5, PI3K phosphorylates the membrane phospholipid PIP2, converting it to PIP3. PIP3 recruits Akt to the membrane and then Akt activates mTOR by inhibiting TSC. Subsequently, mTOR interacts with Raptor, which binds both 4E-BP and S6K. Phosphorylation of S6 and 4E-BP finally results in mRNA translation. ERK is a point of convergence of several signaling cascades. Several FMRP target mRNAs (PP2A and PI3K) are members of second messenger cascades converging on ERK. ERK phosphorylation is regulated by phosphatases such as PP2A. In fmr1-KO mice, PP2A is overactivated after mGluR5 stimulation, causing the rapid deactivation of ERK. The Ca²⁺ stored by IP3 release leads to activation of Ca²⁺-calmodulin (CaM) dependent pathways, including AC1-cAMP dependent protein kinase (PKA) and CaMKIV, which were stimulated by CaM and then phosphorylate CREB. Phosphorylated CREB initiates the CREB-dependent transcription of fmr1 gene and upregulates FMRP. MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal regulated kinase; Mnk1, mitogen-activated protein kinase interacting serine/threonine kinase 1; PI3K, phosphoinositide-3 kinase; 4E-BP, 4E-binding protein; S6K, S6 kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; TSC, tuberous sclerosis complex; GAP, GTPase-activating protein.