**7. References**


Albus, J. S. (1971). A theory of cerebellar function. *Math. Biosci*. Vol.10, pp. 25-61.

Aniksztejn, L. & Ben-Ari, Y. (1991). Novel form of long-term potentiation produced by a K+ channel blocker in the hippocampus. *Nature,* Vol.349, No.6304, pp. 67-9.

*vivo* disturbances of cortical plasticity and excitability in schizophrenia patients. Paired associative stimulation (PAS) induced LTP-like plasticity was disrupted and these plasticity deficits were indicated to be caused by NMDAR abnormalities in schizophrenia patients (Frantseva et al., 2008). Dysfunction of glutamatergic transmission is associated with the pathophysiological state in schizophrenia and this will lead to disturbed plasticity and

Hippocampal LTP in CA1 area was greatly reduced in epilepsy. This reduction was associated with altered dendritic morphology and reduced hippocampal non-spatial memory seen in epileptic mouse model (Sgobio et al., 2010). The composition of ionotropic glutamate receptors in the PSD was found to be altered in brain areas where seizure activity is more pronounced (Wyneken et al., 2003). Application of low frequency stimulation to depoteniate the hyperexcitable synapses were found to be effective in epileptic patients

In drug addiction and fear conditioning related to post traumatic stress disorder, normal LTP and learning are responsible for the undesired condition (Mahan and Ressler, 2011). The impairment of hippocampus-dependent memory retrieval under acute stress condition is mediated by hippocampal LTD (Collingridge et al., 2010). In Fragile X syndrome (FXS), FMRP, is mutated and acts as a negative regulator of *Arc* translation. The dysregulated

A plethora of information thus provide concrete evidence that impairment of synaptic

Although a great deal has been learnt regarding the mechanisms that operate during synaptic plasticity, a complete description of the molecular basis of synaptic plasticity that underlies higher brain functions such as learning and memory is yet to be accomplished. While there is strong experimental support for changes in AMPAR activity as a major post synaptic mechanism supporting plasticity at synapses, the role of presynaptic mechanisms is less understood. The diversity in the mechanisms across different brain regions and across different species is a major challenge towards providing a mechanistic explanation of synaptic plasticity. Understanding the deviations in synaptic plasticity mechanisms in diseases may reveal new targets for the early therapeutic intervention in CNS disorders.

Abraham, W. C., Logan, B., Greenwood, J. M. & Dragunow, M. (2002). Induction and

Aniksztejn, L. & Ben-Ari, Y. (1991). Novel form of long-term potentiation produced by a K+ channel blocker in the hippocampus. *Nature,* Vol.349, No.6304, pp. 67-9.

months in the hippocampus. *J. Neurosci.,* Vol.22, No.21, pp. 9626-34. Abraham, W. C., Logan, B., Wolf, A. & Benuskova, L. (2007). "Heterosynaptic" LTD in the

Albus, J. S. (1971). A theory of cerebellar function. *Math. Biosci*. Vol.10, pp. 25-61.

*Neurophysiol.,* Vol.98, pp. 1048–1051.

experience-dependent consolidation of stable long-term potentiation lasting

Dentate Gyrus of Anesthetized Rat Requires Homosynaptic Activity. *J.* 

neurotoxicity (Hasan et al., 2011; Konradi and Heckers, 2003; Paz, 2008).

expression of *Arc* may alter plasticity (Shepherd & Bear, 2011).

plasticity in diseases can contribute to decline in learning and memory.

(Tergau et al., 1999).

**6. Conclusion** 

**7. References** 


Molecular Mechanisms in Synaptic Plasticity 323

D'Amelio, M., Cavallucci, V., Middei, S., Marchetti, C., Pacioni ,S., Ferri ,A., Diamantini, A.,

mouse model of Alzheimer's disease. *Nature Neuroscience*, Vol.14, pp. 69-76. De Zeeuw, C. I., Hansel, C., Bian, F., Koekkoek, S. K. E., van Alphen, A. M, Linden D. J. &

Derkach, V., Barria, A. & Soderling, T. R. (1999). Ca2+/calmodulin-kinase II enhances

Di Marzo, V., Melck, D., Bisogno, T. & De Petrocellis, L. (1998). Endocannabinoids:

Diana, G., Domenici, M. R., Scotti de Carolis, A., Loizzo, A. & Sagratella, S. (1995). Reduced

Fitzjohn, S. M., Palmer, M. J., May, J. E. R., Neeson, A., Morris, S. A. C. & Collingridge, G. L.

Foster, T. C., & Norris, C. M. (1997). Age-associated changes in Ca (2+)-dependent processes: Relation to hippocampal synaptic plasticity. *Hippocampus,* Vol.7, pp. 602–612. Frey, U., Huang, Y. Y. & Kandel, E. R. (1993). Effects of cAMP simulate a late stage of LTP in

Gladding C. M. (2009). Tyrosine dephosphorylation regulates AMPAR internalization in

Good, T. A., Smith, D. O. & Murphy, R. M. (1996). Beta-amyloid peptide blocks the fast-

Gong, Y., Chang, L., Viola, K. L., Lacor, P. N., Lambert, M. P., Finch, C. E., Krafft, G. A. &

Gong, Y. & Lippa, C. F. (2010). Review: Disruption of the Postsynaptic Density in

Greenough, W. T., Klintsova, A. Y., Irwin, S. A., Galvez, R., Bates, K. E. & Weiler, I. J. (2001).

inactivating K+current in rat hippocampal neurons. *Biophysical Journal,* Vol.70, pp.

Klein, W. L. (2003). Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. *Proc.* 

Alzheimerâs Disease and Other Neurodegenerative Dementias. *American journal of* 

Synaptic regulation of protein synthesis and the fragile X protein. *Proc. Natl. Acad.* 

hippocampal CA1 neurons. *Science,* Vol.260, No.5114, pp. 1661-4.

synaptic tagging. *The EMBO J*., Vol.30, pp. 3540-3552.

mGluR LTD. *Mol. Cell. Neurosci.*, Vol.40, pp. 267-279.

*Natl. Acad. Sci. U S A.,* Vol.100, No.18, pp. 10417–10422.

*Alzheimer's disease and other dementias*, Vol.25, pp. 547-555.

*Sci. U.S.A* Vol.98, pp. 7101–7106.

Vol.20, pp. 495–508.

*Neurosci.,* Vol.21, pp. 521–528.

1745.

pp*.* 421-430*.*

296–304

De Zio, D., Carrara, P., Battistini, L, Moreno, S., Bacci, A., Ammassari-Teule, M., Marie, H. & Cecconi, F. (2011). Caspase-3 triggers early synaptic dysfunction in a

Oberdick, J. (1998). Expression of a Protein Kinase C Inhibitor in Purkinje Cells Blocks Cerebellar LTD and Adaptation of the vestibulo-Ocular Reflex. *Neuron,*

channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. *Proc. Natl. Acad. Sci. U S A,* Vol.96, No.6, pp. 3269-74. Desai, N. S., Casimiro, T. M., Gruber, S. M. & Vanderklish, P. W. (2006). Early postnatal

plasticity in neocortex of Fmr1 knockout mice. *J. Neurophysiol.,* Vol.96, pp. 1734–

endogenous cannabinoid receptor ligands with neuromodulatory action. *Trends* 

hippocampal CA1 Ca(2+)-induced long-term potentiation is associated with agedependent impairment of spatial learning. *Brain Research,* Vol.686, pp. 107–110. Doyle, M. & Kiebler, M. A. (2011). Mechanisms of dendritic mRNA transport and its role in

(2001). A characterization of long-term depression induced by metabotropic glutamate receptor activation in the rat hippocampus *in vitro. J. Physiol.,* Vol*.*537.2*,* 


Bliss, T. V. & Lomo, T. (1973). Long-lasting potentiation of synaptic transmission in the

Blundon, J. A. & Zakharenko, S. S. (2008). Dissecting the components of long-term

Bolshakow, V. Y & Siegelbaum, S. A. (1994). Postsynaptic induction and presynaptic expression of hippocampal long term depression. *Science,* Vol.264, pp. 1148-1152. Bramham, C. R., Alme, M. N., Bittins, M., Kuipers, S. D., Nair, R. R., Pai, B.,·Panja, D.,

Braunewell, K. H. & Manahan-Vaughan, D. (2001). Long-term depression: a cellular basis

Brigman, J. L., Wright, T., Talani, G., Mulcare, S. P., Jinde, S., Seabold, G. K., Mathu, P.,

Bryne, J. H. & Roberts, J. L. (2009). *From Molecules to Networks, An Introduction to Cellular and Molecular Neuroscience,* (Ed.2). Elsevier, ISBN 978-0-12-374132-5, China. Chapman, P. F., White, G. L., Jones, M. W., Cooper-Blacketer, D., Marshall, V. J., Irizarry,

Chen, Q. S., Kagan, B. L., Hirakura, Y. & Xie, C. W. (2000). Impairment of hippocampal long-

Chen, Q. S., Wei, W. Z., Shimahara, T. & Xie, C. W. (2002). Alzheimer amyloid beta peptide

Cheriyan, J., Kumar, P., Mayadevi, M., Surolia, A. & Omkumar, R. V. (2011).

Chung, H. J., Steinberg, J. P., Huganhir, R. L. & Linden, D. J. (2003). Requirement of AMPA

Cissé, M., B., Halabisky, J., Harris, N., Devidze, D. B., Dubal, B., Sun, A., Orr, G., Lotz, D. H.,

Collingridge, G. L., Peineau, S., Howland, J. G. & Wang, Y. T. (2010). Long-term depression

Cooke, S. F. & Bliss, T. V. (2006). Plasticity in the human central nervous system. *Brain,*

*J. Physiol.,* Vol.232, No.2, pp. 331-56.

Vol.30, No.13, pp. 4590–4600.

*Nat. Neurosci*., Vol.l2, pp. 271-276.

*Research,* Vol.60, pp. 65–72.

354 –371.

*One*, Vol.*6*, e16495.

Vol.300, pp. 1751-1755.

Vol.129, No.Pt 7, pp. 1659-73.

Alzheimer model. *Nature,* Vol.469, pp. 47-52.

in the CNS, *Nature Neurosci*., Vol.11, pp. 459-473.

pp. 125-140.

potentiation. *Neuroscientist,* Vol.14, No.6, pp. 598-608.

for learning? *Rev. Neurosci*., Vol.12, pp. 121–140.

dentate area of the anaesthetized rabbit following stimulation of the perforant path.

Schubert, M. & Soule, J. (2010). The *Arc* of synaptic memory. *Exp. Brain Res*, Vol.200,

Davis, M. I., Bock, R., Gustin, R. M., Colbran, R. J., Alvarez, V. A., Nakazawa, K., Delpire, E., Lovinger, D. M. & Holmes,A. (2010). Loss of GluN2B-Containing NMDA Receptors in CA1 Hippocampus and Cortex Impairs Long-Term Depression, Reduces Dendritic Spine Density, and Disrupts Learning. *J. Neurosci.*,

M., Younkin, L., Good, M. A., Bliss, T. V. P. & Hyman, B. T. (1999). Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice*.* 

term potentiation by Alzheimer amyloid beta-peptides. *Journal of Neuroscience* 

inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus. *Neurobiol. Learn. Mem*., Vol.77, pp.

Calcium/calmodulin dependent protein kinase II bound to NMDA receptor 2B subunit exhibits increased ATP affinity and attenuated dephosphorylation. *PLoS* 

receptor GluR2 phosphorylation for cerebellar long term depression. *Science*,

Kim & Hamto, P. (2011). Reversing EphB2 depletion rescues cognitive functions in


Molecular Mechanisms in Synaptic Plasticity 325

Kemp, A. & Manahan-Vaughan, D. (2007). Hippocampal long-term depression: master or

Kim, M. J., Futai, K., Jo, J., Hayashi, Y., Cho, K. & Sheng, M. (2007). Synaptic Accumulation

Klyubin, I., Betts, V., Welzel, A. T., Blennow, K., Zetterberg, H., Wallin, A., Lemere, C. A. ,

Konradi, C. & Heckers, S. (2003). Molecular aspects of glutamate dysregulation: implications

Kullmann, D. M. & Lamsa, K. (2008). Roles of distinct glutamate receptors in induction of anti-hebbian long-term potentiation. *J. Physiol,* Vol.586, No.6, pp. 1481-6. Kumar, A. (2011). Long-term potentiation at CA3–CA1 hippocampal synapses with special

Lamprecht, R. & LeDoux, J. (2004). Structural plasticity and memory. *Nature Reviews* 

Lamsa, K. P., Heeroma, J. H., Somogyi, P., Rusakov, D. A. & Kullmann, D. M. (2007). Anti-

Lee, H. K., Barbaroise, M., Kameyama, K., Bear, M. F. & Huganhir, R. L. (2000). Regulation

Lev- Ram, V., Wong, S. T., Storm, D. R. & Tsein, R. Y. (2002). A new form of cerebellar long

Levy, W. B. & Steward, O. (1979). Synapses as associative memory elements in the

Li, S., Hong, S., Shepardson, N. E., Walsh, D.M., Shankar, G. M. & Selkoe, D. (2009). Soluble

disrupting neuronal glutamate uptake. *Neuron,* Vol.62, No6, pp. 788–801. Lisman, J., Grace, A. A. & Duzel, E. (2011). A neohebbian framework for episodic memory;

Lisman, J., Schulman, H. & Cline, H. ( 2002). The molecular basis of CaMKII function in synaptic and behavioural memory. *Nat. Rev. Neurosci.*, Vol.*3*, pp.1 75-190. Lu, J. T., Li, C. Y., Zhao, J. P., Poo, M. M. & Zhang, X. H. (2007). Spike-timing-dependent

Lu,Y., Ji,Y., Ganeshan, S., Schloesser, R., Martinowich, K., Sun, M., Mei, F., Chao, M, V. &

hippocampal formation. *Brain Res.,* Vol.175, No.2, pp. 233-45.

role of dopamine-dependent late LTP. *Trends in Neurosciences*.

target cell type. *J. Neurosci.,* Vol.27, No.36, pp. 9711-20.

*Neuroscience,* Vol.31(33), pp. 11762-11771.

pp. 111-118.

7258.

10.3389/fnagi.2011.00007

*Neuroscience*, Vol.5, pp. 45-54.

*Science,* Vol.315, No.5816, pp. 1262-6.

plasticity. *Nature,* Vol.405, pp. 955-959.

*Natl. Acad. Sci. USA.,* Vol 99, pp. 8389-8393.

PSD-95. *Neuron,* Vol.56, pp. 488–502

28, No.16, pp. 4231-7, ISSN 0270-6474/08/284231-07.

minion in declarative memory processes? *TRENDS in Neurosciences,* Vol.30 No.3,

of PSD-95 and Synaptic Function Regulated by Phosphorylation of Serine-295 of

Cullen, W. K., Peng, Y., Wisniewski, T., Selkoe, D. J., Anwyl, R., Walsh, D. M. & Rowan, M. J. (2008). Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization. *J. Neurosci.,* Vol.

for schizophrenia and its treatment. *Pharmacol. Ther.,* Vol.97, pp. 153–79, ISSN 0163-

emphasis on aging, disease, and stress. *Front. Ag. Neurosci*., Vol3, Article 7, doi:

hebbian long-term potentiation in the hippocampal feedback inhibitory circuit.

of distinct AMPA receptor phosphorylation sites during bidirectional synaptic

term potentiation is postsynaptic and depends on nitric oxide but not cAMP. *Proc.* 

oligomers of amyloid β protein facilitate hippocampal long-term depression by

plasticity of neocortical excitatory synapses on inhibitory interneurons depends on

Lu, B. (2011) TrkB as a Potential Synaptic and Behavioral Tag. *The journal of* 


Haass, C. & Selkoe, D. J. (1993). Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide*. Cell.,* Dec 17, Vol.75, No.6, pp.1 039-42. Hansel C., de Jeu. M., Belmeguenai. A., Houtman S. H., Buitendijk G. H. S, Andreev, D., De

Harris, J. A., Devidze, N., Halabisky, B., Lo, I., Thwin, M.T., Yu, G. Q., Bredesen, D. E.,

Harrison, P. J. & Weinberger, D. R . (2005). Schizophrenia genes, gene expression and

Hasan, A., Michael, A., Nitscheb, Reina, N., Schneider-Axmanna, T., Gusea, B., Grubera, O.,

Hsia, A. Y., Masliah, E., McConlogue, L., Yu, G. Q, Tatsuno, G., Hu, K., Kholodenko, D.,

Hu, G. Y., Hvalby, O., Walaas, S. I., Albert, K. A., Skjeflo, P., Andersen, P. & Greengard, P.

Hu, N. W., Ondrejcak, T. & Rowan, M. J. (2011). Glutamate receptors in preclinical research

Huang, Y. Y. & Kandel, E. R. (1994). Recruitment of long-lasting and protein kinase a-

Huber, K. M., Kayser, M. S. & Bear, M. F. (2000). Role for rapid dendritic protein synthesis in

Ito, M. (1982). Cerebellar control of the vestibule ocular reflex around the flocculus

Jorntell, H. & Hansel, C. (2006). Synaptic memories upside down: Bidirectional plasticity at

Kandel, E. R. (2001). The molecular biology of memory storage: A dialogue between genes

Kandel, E. R., Schwartz, J. H. & Jessel, T. M. (2000). Principles of Neural Science. (Ed.4).

*Behavioural Brain Research,* Vol.224, pp. 15– 22, ISSN 0166-4328.

of long term potentiation. *Nature,* Vol.328, No 6129, pp. 426-9.

repeated tetanization. *Learn. Mem.,* Vol.1, No.1, pp. 74-82.

hypothesis. *Annu. Rev. Neurosci*., Vol.5, pp. 275-296.

and synapses. *Science,* Vol.294, No.5544, pp. 1030-8.

McGraw-Hill, ISBN 0-8385-7701-6.

motor learning, *Neuron,* Vol*.*51, pp. 835-843.

ISSN 0270-6474.

40–68, ISSN 1359-4184.

Hebb, D. (1949). *The organization of behavior*, pp. 319-340.

Vol.96, No6, pp. 3228–3233.

*Behavior*, ISSN 0091-3057.

1257.

ISSN 0959-4388.

Zeeuw, C. I. & Elgersma Y. (2006). αCaMKII is Essential for Cerebellar LTD and

Masliah, E. & Mucke, L. (2010). Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer's disease are independent of caspase cleavage of the amyloid precursor protein. *J. Neurosci*., Vol.30, No.1, pp. 372–381,

neuropathology: On the matter of their convergence. *Mol. Psychiatry*, Vol.10, pp.

Falkaia, P. & Wobrocka, T. (2011). Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation.

Malenka, R. C., Nicoll, R. A. & Mucke L. (1999). Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models, *Proc. Natl. Acad. Sci. U S A.,*

(1987). Protein kinase C injection into hippocampal pyramidal cells elicits features

on Alzheimer's disease: update on recent advances. *Pharmacology Biochemistry and* 

dependent long-term potentiation in the CA1 region of hippocampus requires

hippocampal mGluR dependent long-term depression. *Science,* Vol.288, pp. 1254–

cerebellar parallel fiber-purkinje cell synapses. *Neuron,* Vol.52, No.2, pp. 227-38,


Molecular Mechanisms in Synaptic Plasticity 327

O'Leary, H., Liu, W. H., Rorabaugh, J. M., Coultrap, S. J. & Bayer, K. U. (2011). Nucleotides

Omkumar, R. V., Kiely, M., Rosentein, A. J., Min, K. T. & Kennedy, M. B. (1996).

Otmakhov, N., Khibnik, L., Otmakhova, N., Carpenter, S., Riahi, S., Asrican, B. & Lisman, J.

Palop, J. J., Chin, J., Roberson, E. D., Wang, J., Thwin, M. T, Bien-Ly, N., Yoo, J., Ho, K. O.,

Palop, J. J. & Mucke, L. (2010). Amyloid-β-induced neuronal dysfunction in Alzheimer's

Park, S., Park, M. J., Kim, S., Kim, J., Shepherd, J. D., Smith- Hicks, C .L., Chowdhury, S.,

Paz, R. D., Tardito, S., Atzori, M. & Tseng, K. Y. 2008. Glutamatergic dysfunction in

Pradeep, K. K., Cheriyan, J., Suma Priya, S. D., Rajeevkumar, R., Mayadevi, M., Praseeda, M.

Proctor, D.T., Coulson, E. J. & Dodd, P. R. (2011). Post-synaptic scaffolding protein

Ramnani, N. (2006). The primate cortico-cerebellar system: anatomy and function. *Nat. Rev.* 

Raymond, C. R. (2008). Different requirements for action potentials in the induction of different forms of long-term potentiation. *J. Physiol,* Vol.586, No.7, pp. 1859-65.

disease, *Progress in Neurobiology,* Vol.93, pp. 509–521, ISSN 0301-0082. Rajeevkumar, R., Suma Priya, S., Mayadevi, M., Mathew Steephan, Santoshkumar ,T. R.,

subunit GluN2B. *J. Biol. Chem.* Vol.286, pp. 31272-31281

dependent. *J. Neurophysiol.,* Vol.91, No.5, pp. 1955-62.

*Neuropsychopharmacol,* Vol.18, pp. 773–86.

Vol.271, pp. 31670-31678

697–711.

812– 818.

pp. 70–83.

123-32.

Vol.110, pp. 92-105.

*Neurosci.,* Vol.7, pp. 511-522.

and phosphorylation bi-directionally modulate Ca2+/calmodulin-dependent protein kinase II (CaMKII) binding to the N-methyl-D-aspartate (NMDA) receptor

Identification of a phosphorylation site for calcium/calmodulin dependent protein kinase II in the NR2B subunit of the N-methyl-D-aspartate receptor. *J. Biol. Chem.*,

(2004). Forskolin-induced LTP in the ca1 hippocampal region is NMDA receptor

Yu, G. Q, Kreitzer, A., Finkbeiner, S., Noebels, J. L. & Mucke, L. (2007). Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. *Neuron,* Vol.55, pp.

disease: from synapses toward neural networks. *Nat. Neurosci*., Vol.13, No.7, pp.

Kaufmann, W., Kuhl, D., Ryazanov, A. G., Huganir, R. L, Linden, D. J. & Worley, P.F. (2008). Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTD. *Neuron,* Vol.59,

schizophrenia: from basic neuroscience to clinical psychopharmacology. *Eur.* 

& Omkumar R, V. (2009). Regulation of Ca2+/calmodulin-dependent protein kinase II catalysis by N-methyl-D-aspartate receptor subunit 2B. *Biochem. J.*, Vol.419, pp.

interactions with glutamate receptors in synaptic dysfunction and Alzheimer's

John Cheriyan, Sanalkumar, R., Pradeep, K. K., Jackson James & Omkumar, R. V. (2009). Phosphorylation status of NR2B subunit of NMDA receptor regulates its interaction with Calcium/calmodulin dependent protein kinase II. *J. Neurochem.,*


Mahan, A. L. & Ressler, K. J. (2011). Fear conditioning, synaptic plasticity and the amygdala:

Malenka, R. C. & Bear, M. F. (2004). LTP and LTD: An embarrassment of riches. *Neuron,*

Malenka, R. C. (2002). Synaptic plasticity. *Neuropsychopharmacology: The Fifth Generation of* 

Malenka, R. C. (2003). The long-term potential of LTP. *Nat. Rev. Neurosci.,* Vol.4, No.11, pp.

Markram, H. (1997). Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs

Martin, S. J., Grimwood, P. D. & Morris, R. G. (2000). Synaptic plasticity and memory: An evaluation of the hypothesis. *Annu. Rev. Neurosci.,* Vol.23, pp. 649-711. Molnar, E. (2011). Long-term potentiation in cultured hippocampal neurons. *Seminars in Cell* 

Montoya, D. A. C. (2011). Synaptic plasticity in Alzheimer's disease: Toward early detection

Moosmang, S., Haider, N., Klugbauer, N., Adelsberger, H., Langwieser, N., Muller, J., Stiess,

Morshita, W., Connor, J. H., Xia, H., Quinlan E, M., Shenolikar, S. & Malenka R. C. (2001).

Mucke, L., Masliah, E., Yu, G. Q., Mallory, M., Rockenstein, E. M., Tatsuno, G., Hu, K.,

Mulkey, R. M., Herron, C. E. & Malenka, R. C. (1993). An essential role for protein phosphatases in hippocampal long-term depression. *Science,* Vol.261, pp. 1051–1055. Nguyen, P. V. & Woo, N. H. (2003). Regulation of hippocampal synaptic plasticity by cyclic amp-dependent protein kinases. *Prog. Neurobiol.,* Vol.71, No.6, pp. 401-37. Nguyen, P. V., Abel, T. & Kandel, E. R. (1994). Requirement of a critical period of transcription for induction of a late phase of ltp. *Science,* Vol.265, No.5175, pp. 1104-7. Nicoll, R. A. & Schmitz, D. (2005). Synaptic plasticity at hippocampal mossy fibre synapses.

Nosyreva, E. D. & Huber, K. M. (2005). Developmental switch in synaptic mechanisms of

Olds, J., Disterhoft, J. F., Segal, M., Kornblith, C. L. & Hirsh, R. (1972). Learning centers of rat

hippocampal metabotropic glutamate receptor-dependent long-term depression. *J.* 

brain mapped by measuring latencies of conditioned unit responses. *J.* 

M., Marais, E., Schulla, V., Lacinova, L., Goebbels, S., Nave, K. A., Storm, D. R., Hofmann, F. & Kleppisch, T. (2005). Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory. *J. Neurosci.,*

Regulation of Synaptic Strength by Protein Phosphatase 1. *Neuron,* Vol.32, pp.1

Kholodenko, D., Johnson-Wood, K. & McConlogue, L. (2000). High-level neuronal expression of A beta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation, *J. Neurosci*., Vol.20, No.11, pp.

Marr, D. (1969). Theory of cerebellar cortex. *J. Physiol*., Vol.202, pp. 437-455.

*and Developmental Biology,*article in press, ISSN 1084-9521

using non-invasive protocols. *Rev. Neurocience*. (Article in press).

press), ISSN 0166-2236

Vol.44, No(1), pp. 5-21.

*Progress,* pp. 147-157.

and EPSPs. *Science,* Vol.275, pp. 213.

Vol.25, No 43, pp. 9883-92.

4050–4058, ISSN 0270-6474.

*Nat. Rev. Neurosci.,* Vol.6, No.11, pp. 863-76.

*Neurosci.,* Vol*.*25, pp. 2992–3001.

*Neurophysiol.,* Vol.35, No.2, pp. 202.

133–1148.

923-6.

implications for post traumatic stress disorder, *Trends in Neurosciences*,(Article in


Molecular Mechanisms in Synaptic Plasticity 329

Stephan, A., Laroche, S. & Davis, S. (2001). Generation of aggregated b-Amyloid in the rat

Strack, S., McNeill R. B & Colbran, R. J. (2000). Mechanism and regulation of

the N-methyl-D-aspartate receptor. *J. Biol. chem.,* Vol.273, pp. 23789-23806. Sweatt, J. D. (2010). *Mechanisms of memory*. Academic press, U.K., 2 nd Edition, ISBN 978-012-

Tackenberg, C. & Brandt, R. (2009). Divergent pathways mediate spine alterations and cell

Tergau, F., Naumann, U., Paulus, W. & Steinhoff, B. J. (1999). Low-frequency repetitive

Teyler, T. J. & Discenna, P. (1987). Long-term potentiation. *Annu Rev Neurosci,* Vol.10, pp.

Tiron ,A. & Wibrand, K. (2010). The Arc of synaptic memory. *Exp. Brain Res.,* Vol.200, pp.

Ueda, K., Shinohara, S., Yagami, T., Asakura, K. & Kawasaki, K. (1997). Amyloid beta

Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S, Rowan, M. J.

in rat dentate gyrus, *Brain Res*., Vol.924, No.2, pp. 133–140, ISSN 0006-8993. Wang, Q., Rowan, M. J. & Anwy, l. R. (2004). Beta-amyloid-mediated inhibition of NMDA

*Neurosci.*, Vol.24, No.27, pp. 6049–6056, ISSN 0270-6474/04/246049-08. West, A. E., Chen, W. G., Dalva, M. B., Dolmetsch, R. E., Kornhauser, J. M., Shaywitz, A. J.,

gene expression. *Proc. Natl. Acad. Sci. USA.,* Vol.98, No.20, pp. 11024-31. Williams, J. H., Errington, M. L., Lynch, M. A. & Bliss, T. V. (1989). Arachidonic acid induces

Woo, N. H., Teng, H. K., Siao, C. J., Chiaruttini, C., Pang, P. T ., Milner, T. A., Hempstead, B.

long-term depression. *Nature Neuroscience,* Vol.8, pp. 1069 - 1077.

hippocampus. *Nature,* Vol.341, No.6244, pp. 739-42.

possible involvement of free radicals. *J. Neurochem.,* Vol.68, pp. 265–271. Vogt, K. E. & Canepari, M. (2010). On the Induction of Postsynaptic Granule Cell – Purkinje

Neuron LTP and LTD. *The Cerebellum,*Vol.9, No.3, pp. 284-90.

deficits, *J. Neurosci*, Vol.21, No.15, pp. 5703–5714.

No.46, pp. 14439 –14450, ISSN 0270-6474/09/291443.

374951-2.

pp. 2209.

131-61.

125-140.

hippocampus impairs synaptic transmission and plasticity and causes memory

calcium/calmodulin dependent protein kinase II targeting to the NR2B subunit of

death induced by amyloid-β, wild-type tau, and R406W tau, *J. Neurosci*., Vol.29,

transcranial magnetic stimulation improves intractable epilepsy. *Lancet,* Vol.353,

protein potentiates Ca 2+ influx through L-type voltage-sensitive Ca2+ channels: A

& Selkoe, D. J. (2002). Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo, *Nature,* Vol.416, pp. 535-539. Wang, H. W., Pasternak, J. F., Kuo, H., Ristic, H., Lambert, M. P., Chromy, B., Viola, K. L.,

Klein, W. L., Stine, W. B., Krafft, G. A. & Trommer, B. L. (2002). Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression

receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J.

Takasu, M. A., Tao, X. & Greenberg, M. E. (2001). Calcium regulation of neuronal

a long-term activity-dependent enhancement of synaptic transmission in the

L. & Bai Lu. (2005). Activation of p75NTR by proBDNF facilitates hippocampal


Reymann, K. G. & Frey, J. U. (2007). The late maintenance of hippocampal LTP:

Roberson, E. D., Halabisky, B., Jong, W., Yoo., Yao, J., Chin, J., Yan, F., Wu, T., Hamto, P.,

Rygh, L, J., Svendsen, F., Fiska, A., Haugan, F., Hole, K. & Tjølsen, A. (2005). Long-term

Schonewille, M., Gao, Z., Henk-Jan Boele., Vinueza Veloz M, F., Amerika W, E., Simek A. A.

Scoville, W. B. & Milner, B. (1957). Loss of recent memory after bilateral hippocampal lesions. *Journal of Neurology, Neurosurgery & Psychiatry,* Vol.20, No.1, pp. 11. Selkoe, D. J. (2008). Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. *Behav. Brain Res.,* Vol.192, pp. 106–113, ISSN 0166-4328. Sgobio, C., Ghiglieri, V., Cinzia Costa, C., Bagetta, V., Siliquini, S., Barone, I.,Filippo, M.,

*Neuropharmacology,* Vol.52, No.1, pp. 24-40.

*Psychoneuroendocrinology*, Vol.30, pp. 959-964.

Motor Learning, *Neuron,* Vol.70, pp. 43–50.

*Nature medicine,* Vol.14, pp. 837-842.

*Nat. Neurosci.,* Vol*.*4. pp. 1079–1085.

0270-6474.

No.2, pp. 700 –711, ISSN 0270-6474.

Requirements, phases, 'synaptic tagging', 'late-associativity' and implications.

Devidze, N., Yu, G., Palop, J. J., Noebels, J. L. & Mucke, L. (2011). Amyloid-β/Fyn– induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse, models of Alzheimer's disease, *The Journal of Neuroscience*, Vol.31,

potentiation in spinal nociceptive systems—how acute pain may become chronic.

M., De Jeu, M. T., Steinberg, J. P., Takamiya, K., Hoebeek, F. E., Linden, D. J,. Huganir, R. L. & De Zeeuw, C. I. (2011). Reevaluating the Role of LTD in Cerebellar

Gardoni, F., Gundelfinger, E. D., Di Luca, M., Picconi, B. & Calabresi, P. (2010). Hippocampal synaptic plasticity, memory, and epilepsy: Effects of long-term valproic acid treatment, *Biol. Psychiatry*., Vol.67, pp. 567–574, ISSN 0006-3223. Shankar, G. M., Bloodgood, B. L., Townsend, M., Walsh, D. M., Selkoe, D. J. & Sabatini, B. L

(2007). Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent

F. M., Farrell, M. A., Rowan M. J. & Lemere C. A. (2008). Amyloid- protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.

F., Hana, N., Dawson, H. N, Vitek, M. P, Wade-Martins, R., Paulsen, O. & Vargas-Caballero, M. (2011). Tau protein is required for amyloid β-induced impairment of hippocampal long-term potentiation, *J. Neurosci*, Vol.31, No.5, pp. 1688 –1692, ISSN

term potentiation occurs only when the ratio of NMDA transmission to AMPA

Internalization of ionotropic glutamate receptors in response to mGluR activation.

signaling pathway. *J. Neurosci.,* Vol.27, pp. 2866–2875, ISSN 0270-6474. Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett,

Shepherd, J. D. & Bear, M. F. (2011). New views of Arc, a master regulator of synaptic

Shipton, O. A., Leitz, J. R., Dworzak, J., Christine, E. J. Acton,C. E., Tunbridge, E. M., Denk,

Smith, C. C. & Mcmahon, L. L. (2005). Estrogen-induced increase in the magnitude of long-

Snyder, E. M., Philpot, B. D., Huber, K. M.,Dong, X., Fallon, J. R., & Bear, M. F. (2001).

transmission is increased. *J. Neurosci,* Vol.25, No.34, pp. 7780-91.

plasticity, *Nature Neuroscience,* Vol.14, No.3, pp. 279-284.


**14** 

*Chile* 

**Brain Energy Metabolism** 

*Instituto de Bioquímica y Microbiología, Facultad de Ciencias,* 

Living cells require energy to perform work, to maintain their organized structures, to synthesize cellular components, to generate electric currents and many other processes. Energy metabolism is a highly coordinated cellular activity in which enzymes are organized into discrete metabolic pathways that cooperate in degrading energy-rich nutrients from the environment. Glucose is the principal metabolic substrate for living cells including brain cells. It is rich in potential energy and is also a versatile precursor, giving rise to metabolic intermediaries for biosynthetic reactions. Glycogen is a polymer of glucose and is the form in which glucose is stored. The mammalian brain contains glycogen, which is located predominantly in astrocytes (Brown & Ransom, 2007). In particular situations, substrates other than glucose can be utilized by the brain. -hydroxybutyrate, acetoacetate and acetone are ketone bodies produced in the liver from Acetyl-CoA. Ketone bodies are an important source of brain energy in breast-fed neonates and during starvation when carbohydrates are scarce. However, it has been proposed that part of brain energy comes from the conversion of glucose to lactate at one location (within one cell) and part comes from the oxidation of

lactate to pyruvate at another location (within the same cell or in a different cell).

The brain makes up 2% of a person's weight. Despite this, even at rest, the brain consumes 25% of the body's energy. Most of the energy consumed in the brain is attributable to restoration of the membrane gradient following neuronal depolarization. Neurotransmitter recycling, intracellular signaling and dendritic and axonal transport also require energy (Attwell & Laughlin, 2001). Even though neurons are responsible for massive energy consumption, the brain is made up of many cells*,* including neurons, glial and ependymal cells. Every brain cell has a specific function and thus every brain cell has different metabolic needs. Many of these specific functions are concerned with maintainance of neuronal transmission. For example, astrocytes play a central role in supporting neurons metabolically by producing lactate, through glycolysis and activation of glycogen catabolism (Brown & Ransom, 2007). Another critical factor for maintenance of neuronal

**1. Introduction** 

 \*

Corresponding Author

 **in Health and Disease** 

Felipe A. Beltrán, Aníbal I. Acuña, María Paz Miró and Maite A. Castro\*

 *Universidad Austral de Chile, Valdivia,* 

