Journal of Neural Transmission. Supplementa

Department of BioMedical Sciences, Modena, Italy.
Journal of neural transmission. Supplementum (Impact Factor: 1.07). 02/2003; 65(65):1-28. DOI: 10.1007/978-3-7091-0643-3_1
Source: PubMed


Learning in neuronal networks occurs by instructions to the neurons to change their synaptic weights (i.e., efficacies). According to the present model a molecular mechanism that can contribute to change synaptic weights may be represented by multiple interactions between membrane receptors forming aggregates (receptor mosaics) via oligomerization at both pre- and post-synaptic level. These assemblies of receptors together with inter alia single receptors, adapter proteins, G-proteins and ion channels form the membrane bound part of a complex three-dimensional (3D) molecular circuit, the cytoplasmic part of which consists especially of protein kinases, protein phosphatases and phosphoproteins. It is suggested that this molecular circuit has the capability to learn and store information. Thus, engram formation will depend on the resetting of 3D molecular circuits via the formation of new receptor mosaics capable of addressing the transduction of the chemical messages impinging on the cell membrane to certain sets of G-proteins. Short-term memory occurs by a transient stabilization of the receptor mosaics producing the appropriate change in the synaptic weight. Engram consolidation (long-term memory) may involve intracellular signals that translocate to the nucleus to cause the activation of immediate early genes and subsequent formation of postulated adapter proteins which stabilize the receptor mosaics with the formation of long-lived heteromeric receptor complexes. The receptor mosaic hypothesis of the engram formation has been formulated in agreement with the Hebbian rule and gives a novel molecular basis for it by postulating that the pre-synaptic activity change in transmitter and modulator release reorganizes the receptor mosaics at post-synaptic level and subsequently at pre-synaptic level with the formation of novel 3D molecular circuits leading to a different integration of chemical signals impinging on pre- and post-synaptic membranes hence leading to a new value of the synaptic weight. Engram retrieval is brought about by the scanning of the target networks by the highly divergent arousal systems. Hence, a continuous reverberating process occurs both at the level of the neural networks as well as at the level of the 3D molecular circuits within each neuron of the network until the appropriate tuning of the synaptic weights is obtained and, subsequently, the reappearance of the engram occurs. Learning and memory in the basal ganglia is discussed in the frame of the present hypothesis. It is proposed that formation of long-term memories (consolidated receptor mosaics) in the plasma membranes of the striosomal GABA neurons may play a major role in the motivational learning of motor skills of relevance for survival. In conclusion, long-lived heteromeric receptor complexes of high order may be crucial for learning, memory and retrieval processes, where extensive reciprocal feedback loops give rise to coherent synchronized neural activity (binding) essential for a sophisticated information handling by the central nervous system.

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    • "According to recent bioinformatic studies (Tarakanov et al. 2012 abcd), several triplet homologies of such receptor heteromers in human brain may be the same as in cell-adhesion receptors of marine sponges, known to be highly conserved from the lowest metazoa to vertebrates (Gamulin et al. 1994; Muller 1997; Pancer et al. 1997; Buljan and Bateman 2009). Interactions between such triplets probably represent a general molecular mechanism for receptor-receptor interactions (Fuxe et al 2012) and may play an important role in human learning (Agnati et al. 2003) and some diseases (Tarakanov et al. 2009). "
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    ABSTRACT: Based on our theory, main triplets of amino acid residues have been discovered in cell-adhesion receptors (integrins) of marine sponges, which participate as homologies in the interface between two major immune molecules, MHC class I (MHCI) and CD8αβ. They appear as homologies also in several human neural receptor heteromers and subunits. The obtained results probably mean that neural and immune receptors also utilize these structural integrin triplets to form heteromers and ion channels, which are required for a tuned and integrated intracellular and intercellular communication and a communication between cells and the extracellular matrix with an origin in sponges, the oldest multicellular animals.
    Full-text · Article · Dec 2013 · SpringerPlus
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    • "Thus, in evolution also the ligand–receptor interactions may have developed from or just repeat the discovery of these protriplets of the cell-adhesion receptors of marine sponges. It should also be considered that the development of such triplets for GPCR oligomerization evolution is a late step in brain evolution which is reasonable based on the theory that heteromerization is part of the molecular basis for learning and memory (Agnati et al. 2003). Fig. 3 Example of the triplet RAA and its inversion AAR (darkshaded letters) in the integrin of marine sponge, human repeat protein ankyrin (ANK), serotonin receptor (5HT1A), fibroblast growth factor (FGF2), and intracellular binding site of its receptor (FGFR1); asterisk marks homologies (A) Table 4 Example of integrin triplets of marine sponges in different types of human proteins "
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    ABSTRACT: Based on our theory, we have discovered main triplets of amino acid residues in cell-adhesion receptors of marine sponges, which appear also as homologies in several receptor heteromers of human brain. The obtained results strengthen our hypothesis that these triplets may "guide-and-clasp" receptor-receptor interactions.
    Full-text · Article · May 2012 · Journal of Molecular Neuroscience
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    • "These parameters can affect both the acquisition of the active state by the receptor and the effector to be activated. Because RMs are connected with effector proteins (e.g., enzymes and ion channels) and work as an integrative unit in HMNs, it has been proposed that RMs at the synaptic level can affect the efficacy of the synaptic transmission (synaptic weight) and therefore might have a role in learning and memory processes (see below; Agnati et al., 2002, 2003b). This was the basic idea that led us to introduce the RM hypothesis of the engram (Agnati et al., 1982). "
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    ABSTRACT: Some theoretical aspects on structure and function of proteins have been discussed previously. Proteins form multimeric complexes, as they have the capability of binding other proteins (Lego property) resulting in multimeric complexes capable of emergent functions. Multimeric proteins might have either a genomic or a postgenomic origin. Proteins spanning the plasma membrane have been analyzed by considering the effects of the microenvironment in which the protein is embedded. In particular, the different effects of the hydrophilic (extracellular and intracellular) versus the lipophilic (intramembrane) environment have been considered. These aspects have been discussed in the framework of membrane microdomains, in particular, the so-called rafts. In alpha-helix proteins the individual peptide dipoles align to produce a macrodipole crossing the entire membrane. This macrodipole has its positive (extracellular) pole at the N-terminal end of the helix and its negative (intracellular) pole at the C-terminal end. This arrangement has been analyzed in the framework of the counter-ion atmosphere, that is, the formation of a cloud of small ions bearing an opposite charge. Excitable cells reverse their resting potential during the all-or-none action potentials. Hence, the extracellular side of the plasma membrane becomes negative with respect to the intracellular side. This change of polarization affects also the direction and magnitude of the alpha-helix dipole in view of the fact that there is a displacement of the counter ions. The oscillation in the intensity of the dipole caused by the action potentials opens the possibility of an interaction among dipoles by electromagnetic waves.
    Full-text · Article · Feb 2005 · Journal of Molecular Neuroscience
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