a) Normal learning

1. BAX BAX BAD CASP3 CASP3 pCASP9 pCASP9 BAX pCASP9 BCL2 BAD BAD BCL2 BCL2 CASP3 BAD BAX BAX BCL2 BAX pCASP9 CASP3 CASP3 pCASP9 pCASP9 BAD BCL2 BAD CASP3 BCL2 Supplementary Figure S1. Hippocampus, Apoptosis related proteins a) Normal learning b) Memantine c) Normal learning + Memantine Nuclear Cytosolic

2. ITSN1 SOD1 ITSN1 ITSN1 SOD1 SOD1 nNOS TH SNCA SHH DYRK1A GAD2 Ubiquitin TH TH SHH GFAP SNCA GAD2 GFAP nNOS GFAP nNOS SHH GAD2 SNCA Ubiquitin DYRK1A Ubiquitin DYRK1A SOD1 SOD1 GFAP ITSN1 SOD1 SHH ITSN1 SNCA TH TH DYRK1A Ubiquitin SHH GAD2 GFAP nNOS SNCA SHH ITSN1 SNCA GFAP TH DYRK1A nNOS DYRK1A Ubiquitin nNOS Ubiquitin GAD2 GAD2 Supplementary Figure S2. Hippocampus, Miscellaneous proteins a) Normal learning b) Memantine c) Normal learning + Memantine Nuclear Cytosolic

3. BRAF pS6 ELK JNK P38 ERK RSK MTOR MEK AKT pERK CREB pMEK pAKT pRSK pEIF4B pCREB AMPKA pBRAF pMTOR CAMKII RAPTOR pELK pCAMKII GSK3B pJNK pGSK3B_S9 PKCA P70S6 pPKCA/B pPKCG S6 pGSK3B_Tyr216 pP70S6 pPKCA/B pBRAF pP70S6 pCREB CREB S6 RSK P38 pS6 ERK JNK AKT pRSK ELK pJNK pAKT MEK pMEK MTOR pEIF4B AMPKA pMTOR RAPTOR pCAMKII PKCA CAMKII pERK GSK3B pGSK3B_S9 P70S6 pPKCG pELK pGSK3B_Tyr216 BRAF pERK BRAF pRSK pP70S6 pPKCG PKCA pS6 ELK AKT JNK P38 MEK pMEK CREB pEIF4B pBRAF pELK RSK pCREB CAMKII RAPTOR pAKT ERK GSK3B pGSK3B_S9 MTOR AMPKA pJNK pMTOR pCAMKII S6 pGSK3B_Tyr216 P70S6 pPKCA/B Supplementary FigureS3. Cortex, Cytosol-MAPK and MTOR MAPK MTOR a) Normal learning b) Memantine c) Normal learning + Memantine

4. RCAN1 Tau PP2A FYN Tau FYN Tau FYN APP APP CaNA PP2A pSRC pSRC PP2A CDK5 CaNA pSRC CDK5 P35/25 ERBB4 CTNNB1 RCAN1 IL1B RCAN1 P35/25 CTNNB1 ERBB4 CDK5 APP IL1B ERBB4 P35/25 IL1B CTNNB1 CaNA PP2A RCAN1 FYN Tau RCAN1 APP CaNA pSRC CDK5 PP2A ERBB4 CTNNB1 Tau P35/25 IL1B RCAN1 Tau APP APP FYN FYN PP2A pSRC pSRC ERBB4 ERBB4 P35/25 CDK5 CTNNB1 CTNNB1 CDK5 IL1B IL1B CaNA CaNA P35/25 CaNA APP CDK5 RCAN1 CaNA ERBB4 FYN CDK5 ERBB4 RCAN1 CTNNB1 FYN APP CaNA CTNNB1 CDK5 ERBB4 APP RCAN1 CTNNB1 FYN Supplementary Figure S4. Cortex, AD related proteins c) Normal learning + Memantine a) Normal learning b) Memantine Nuclear Cytosol Membrane

5. PSD95 NR1 NR2A pNR1 NR2B TIAM1 TRKA BDNF pNR2B pNUMB GLUR3 GLUR4 NUMB pGLUR2 CAMKII pCAMKII pNR2A NR1 NR2A TIAM1 pNR1 NR2B pNR2A pNUMB GLUR3 GLUR4 pGLUR2 pCAMKII PSD95 NUMB CAMKII BDNF pNR2B TRKA PSD95 NR1 TRKA BDNF pNUMB pNR2B GLUR3 GLUR4 pGLUR2 CAMKII pNR1 NUMB TIAM1 NR2B NR2A pNR2A pCAMKII Supplementary Figure S5. Cortex, Cytosol-NMDA receptor subunits and related proteins a) Normal learning b) Memantine c) Normal learning + Memantine

6. CFOS pCFOS H3 (AcK18) ARC EGR1 H3 (AcK9) H3 (MeK4) CFOS pCFOS EGR1 ARC H3 (MeK4) H3 (AcK18) H3 (AcK9) H3 (AcK9) CFOS ARC EGR1 pCFOS H3 (AcK18) H3 (MeK4) Supplementary Figure S6. Cortex, Nuclear-IEgs and Histone modifications proteins a) Normal learning b) Memantine c) Normal learning + Memantine

7. CASP3 BAD BAD BCL2 CASP3 CASP3 pCASP9 BAX BAX pCASP9 pCASP9 BAD BCL2 BAX BCL2 BAD BAD BAX BCL2 BCL2 CASP3 BAX CASP3 pCASP9 BAD BAX BCL2 CASP3 pCASP9 pCASP9 Supplementary Figure S7, Cortex, Apoptosis related proteins a) Normal learning b) Memantine c) Normal learning + Memantine Nuclear Cytosolic

8. SOD1 GAD2 SOD1 TH SNCA SOD1 Ubiquitin TH GFAP GAD2 ITSN1 GFAP nNOS ITSN1 DYRK1A DYRK1A SHH SHH TH SNCA nNOS SHH ITSN1 GFAP GAD2 Ubiquitin nNOS DYRK1A SNCA Ubiquitin SOD1 SOD1 DYRK1A GFAP SOD1 DYRK1A TH SHH TH nNOS SNCA SHH SNCA nNOS GAD2 GFAP TH Ubiquitin Ubiquitin SHH SNCA nNOS GFAP Ubiquitin ITSN1 GAD2 ITSN1 ITSN1 DYRK1A GAD2 Supplementary Figure S8. Cortex, Miscellaneous proteins b) Memantine c) Normal learning + Memantine a) Normal learning Nuclear Cytosolic