Fig 1.
Schematic model of the signaling pathways essential to consolidation of IA long-term memory (LTM).
(A) Signaling pathways with multiple feedback loops, including positive BDNF-CaMKIIα (blue) and BDNF-C/EBPβ (green) feedback loops that contribute to memory consolidation. MeCP2, HDAC2 and Sin3a bi-directionally regulate BDNF expression (red). Details and equations are given in the main text. (B) Scheme of interactions among bound Sin3a (red), MeCP2 (purple) and HDAC2 (blue), and their effects on the bdnf exon IV promoter. Arrowheads indicate activation, circular ends indicate repression.
Table 1.
Standard parameter values.
Fig 2.
Simulated effects of increased pCREB combined with decreased pCaMKIIα on time courses of molecular pathways and synaptic weight W after IA training.
(A1) Modifications of the model of the molecular pathways for IA conditioning, including increased basal phosphorylation of CREB, kbasalp_creb, concurrent with decreased basal phosphorylation of CaMKIIα, kbasalp_CaMKII (red arrows). (A2) 3D plot of synaptic weight W at day 7 after training with kbasalp_creb increasing from the standard value in Table 1 to 300% of the standard value, and kbasalp_CaMKII decreasing from the standard value in Table 1 to 50% of the standard value, with increased binding of MeCP2, Sin3a and HDAC2 (A2). The light blue area represents W less than 200% of basal level. (B) Example of dynamics of BDNF protein/mRNA (B1-2), C/EBPβ protein (B3), pCREB (B4), pCaMKIIα (B5), Sin3a binding (B6), MeCP2 binding (B7), HDAC2 binding (B8), and W (B9), with the standard parameter values in Table 1 (black dashed) or with kbasalp_creb increased by ~50% and kbasalp_CaMKII decreased by ~50% from control combined with higher binding levels of MeCP2, Sin3a and HDAC2 (blue) to simulate IA conditioning in infant rats. Gray dashed line in (B9) represents W at 200% control.
Fig 3.
(A) Schematic model of the pathways that are blocked by PSI (red X’s). (B) Reduction of synaptic weight W at day 2 (blue curve) and 7 (red curve) after training, with the addition of PSI initiated at varying times. ‘1’,’2’,’3’ represent different phases. (C-D) Simulated reduction of W response to PSI in the absence of the BDNF-CaMKIIα feedback loop (C) or of the BDNF-C/EBPβ feedback loop (D) or of the downstream W loop (E) at day 2 (blue) and day 7 (red). Insert in (E), same as main panel except Y axis scale is expanded to more clearly illustrate vertical variations in W.
Fig 4.
Simulated dynamics of model variables when PSI was added 25 h or 35 h post-stimulus.
Example of dynamics of BDNF protein/mRNA (A-B), C/EBPβ protein (C), pCREB (D), pCaMKIIα (E), and Sin3a binding (F), MeCP2 binding (G), HDAC2 binding (H), Tag (I), GROD (J), PP (K), and W (L), without PSI (black dashed) or with PSI added at 25 h post- stimulus (blue), or at 35 h post- stimulus (red).
Fig 5.
Simulated effects of various parameters on the multiple phases of W resistance in response to PSI.
The dynamics of reduction of W at day 2 and 7 post-stimulus, with the addition of PSI initiated from 0 h to 48 h, varied when altering τComp (A), τE_MeCP2 (B), τHDAC2 (C), rSin3a (D), τTag (E), τGPROD (F). ‘1’,’2’,’3’ represent different phases.