Knafo S, Venero C, Sánchez-Puelles C, Pereda-Peréz I, Franco A, Sandi C, Suárez LM, Solís JM, Alonso-Nanclares L, Martín ED, Merino-Serrais P, Borcel E, Li S, Chen Y, Gonzalez-Soriano J, Berezin V, Bock E, Defelipe J, Esteban JA.
Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement.
PLoS Biol. 2012 Feb;10(2):e1001262.
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These studies explore the cognition-enhancing actions of a peptide agonist of the neural cell adhesion molecule (NCAM), the FG loop (FGL) peptide, synthesized from the second fibronectin type III module of NCAM. The identification of FGL as a cognition-enhancing agent is well established in the literature, and this new and most comprehensive dataset now provides further information on the molecular mechanisms by which this peptide may mediate its action. The bottom line outcome of these studies is that FGL enhances cognition in rodents and long-term potentiation (LTP), a cellular model of memory and learning, in hippocampal slices. This facilitation is demonstrated to be mediated by FGL enhancing the delivery of AMPA-type glutamate receptor into excitatory synapses following activation of NMDA-type glutamate receptors. Importantly, these effects are reported to be specifically mediated by PKC activation.
This new dataset opens up pathways (literally) to further experiments such as the effect of the FGL peptide on the polysialylation status of NCAM, which also regulates plasticity and learning through modulation of NMDA receptor signaling using the GluN2B-Ras-GRF1-p38 MAPK pathway (Kochlamazashvili et al., 2010). Understanding crosstalk, if any, between these two pathways may be crucial to revealing core neuroplastic deficits in Alzheimer’s disease, in which postmortem studies have shown NCAM polysialylation to be significantly increased in the hippocampal formation (Mikkonen et al., 1999).
Secondly, it is of particular interest that, despite a most rigorous morphological analysis, the FGL peptide fails to have any impact on synapse density in the CA1 region of the hippocampus. This finding is consistent with previous studies on the effect of FGL on plasticity in the dentate and CA3 regions of the hippocampus (Popov et al., 2008; Ojo et al., 2011)—as an aside, the dentate study found an increase in the frequency of coated pits, which would be consistent with the AMPA receptor trafficking data reported in this PLoS Biology paper. The synaptic plasticity mediated by the FGL agonist, therefore, would appear to relate to retuning the strength of existing cell synapses in which the learning and memory networks are distinguished by the composition of the cells that are coactivated. This contrasts with the synapse assembly mechanism in which the creation and pruning of synapses elaborates a network of specific groups of novel synapses with a connectivity scheme that has been optimized for each response (Ziv and Ahissar, 2009).
As a consequence, the nature of the synaptic plasticity wrought by novel drug strategies, such as that of the FGL peptide, may have significant implications for their future clinical development. Drugs that augment synapse elaboration mechanisms, for example, may have greater impact on neurodegenerative conditions such as Alzheimer’s disease, in which neuron loss and synapse loss provide the neuropathological correlative for dementia (DeKosky and Scheff, 1990). The FGL peptide agonist, which is known to be well tolerated in humans (Anand et al., 2007), primarily appears to retune the strength of existing cell synapses and, as such, may have more relevant neurotherapeutic potential in conditions other than Alzheimer’s disease. A role for FGL in the treatment of depression has been previously suggested by the authors (Aonurm-Helm et al., 2008).
Anand R, Seiberling M, Kamtchoua T, Pokorny R.
Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers.
Clin Pharmacokinet. 2007;46(4):351-8.
Aonurm-Helm A, Jurgenson M, Zharkovsky T, Sonn K, Berezin V, Bock E, Zharkovsky A.
Depression-like behaviour in neural cell adhesion molecule (NCAM)-deficient mice and its reversal by an NCAM-derived peptide, FGL.
Eur J Neurosci. 2008 Oct;28(8):1618-28.
Dekosky ST, Scheff SW.
Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity.
Ann Neurol. 1990 May;27(5):457-64.
Kochlamazashvili G, Senkov O, Grebenyuk S, Robinson C, Xiao MF, Stummeyer K, Gerardy-Schahn R, Engel AK, Feig L, Semyanov A, Suppiramaniam V, Schachner M, Dityatev A.
Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors.
J Neurosci. 2010 Mar 17;30(11):4171-83.
Mikkonen M, Soininen H, Tapiola T, Alafuzoff I, Miettinen R.
Hippocampal plasticity in Alzheimer's disease: changes in highly polysialylated NCAM immunoreactivity in the hippocampal formation.
Eur J Neurosci. 1999 May;11(5):1754-64.
Ojo B, Rezaie P, Gabbott PL, Davies H, Colyer F, Cowley TR, Lynch M, Stewart MG.
Age-related changes in the hippocampus (loss of synaptophysin and glial-synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL.
Brain Behav Immun. 2011 Oct 2;
Popov VI, Medvedev NI, Kraev IV, Gabbott PL, Davies HA, Lynch M, Cowley TR, Berezin V, Bock E, Stewart MG.
A cell adhesion molecule mimetic, FGL peptide, induces alterations in synapse and dendritic spine structure in the dentate gyrus of aged rats: a three-dimensional ultrastructural study.
Eur J Neurosci. 2008 Jan;27(2):301-14.
Ziv NE, Ahissar E.
Neuroscience: New tricks and old spines.
Nature. 2009 Dec 17;462(7275):859-61.