Possible role of intramembrane receptor-receptor interactions in memory and learning via formation of long-lived heteromeric complexes: focus on motor learning in the basal ganglia.
ABSTRACT 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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ABSTRACT: In this paper a hypothesis that some special signals (“key-signals” excito-amino acids, β-amyloid peptides and α-synuclein) are not only involved in information handling by the neuronal circuits, but also trigger out substantial structural and/or functional changes in the Central Nervous System (CNS) is introduced. This forces the neuronal circuits to move from one stable state towards a new state, but in doing so these signals became potentially dangerous. Several mechanisms are put in action to protect neurons and glial cells from these potentially harmful signals. However, in agreement with the Red Queen Theory of Ageing (Agnati et al. in Acta Physiol Scand 145:301–309, 1992), it is proposed that during ageing these neuroprotective processes become less effective while, in the meantime, a shortage of brain plasticity occurs together with an increased need of plasticity for repairing the wear and tear of the CNS. The paper presents findings supporting the concept that such key-signals in instances such as ageing may favour neurodegenerative processes in an attempt of maximizing neuronal plasticity.Journal of Neural Transmission 01/2009; 116(8):953-974. · 3.05 Impact Factor
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ABSTRACT: The major difference of synaptic transmission vs volume transmission (VT) is about the channels which are private in synaptic transmission (axons and terminals) but diffuse in VT represented by the channel plexus of the extracellular space and the CSF. There exist different forms of VT: extrasynatic, long distance, CSF and roamer type VT, the last one mediated via microvesicles (extracellular vesicles). Interleukin-1β (IL-1β) may produce inflammation and sickness behavior via long distance and CSF VT. The balance and integration of VT and synaptic transmission through receptor–receptor interactions in heteroreceptor complexes appears crucial for CNS communication and of high relevance for psychiatric diseases like schizophrenia, depression, cocaine addiction and anxiety. The allosteric receptor–receptor mechanism causes a marked rise of the repertoire of GPCR recognition, pharmacology, trafficking and signaling of the participating receptor protomers. We have introduced the moonlighting concept into the GPCR heteromer field, since GPCR protomers can change their function through the allosteric receptor–receptor interactions. This is achieved through changes in recognition, G protein selectivity, and signaling via other proteins involving, e.g., a switch from G proteins to β-arrestin through conformational changes in single or several strands of amino acids. It is of substantial interest to understand the role of altered receptor–receptor interactions as a mechanism for how neuroinflammatory processes can contribute to mental dysfunctions. It is hypothesized that chemokine and cytokine receptors may directly form heteroreceptor complexes with neuronal receptors known to be dysfunctional in schizophrenia and targets for antipsychotic drugs. Based on the current bioinformatic analysis performed we can postulate that chemokine receptor CXCR4 may directly interact with GABAB2 and NR2A subunits of the NMDAR, chemokine receptor CCR2 with NMDAR, GABAB1 subunit and GABAAR and cytokine receptor IL1R2 with GABAB1 subunit and NMDAR, all known to be involved in schizophrenia. Through the allosteric receptor–receptor interactions in such pathological heteroreceptor complexes the neuronal NMDA, GABAA and GABAB protomers may change their function (moonlighting) in neuronal networks of the brain. This process in neuroinflammation can contribute to positive, negative and/or cognitive symptoms of schizophrenia in line with the mild encephalitis hypothesis of schizophrenia. Neuroinflammation in schizophrenia may also disturb the integrative process of synaptic and volume transmission signals in glutamate synapses by altering kynurenines in the mammalian brain.Neurology Psychiatry and Brain Research 12/2013; 19(4):141–158. · 0.13 Impact Factor
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ABSTRACT: The phenomenon of receptor-receptor interactions was hypothesized by Agnati and Fuxe in the 1980s, and several indirect proofs were provided in the following years by means of in vitro binding experiments and in vivo experiments in physiological and pathological animal models. This paper aims to outline some of the most important features and consequences of this phenomenon in the frame of the structural and functional aspects of molecular networks. In particular, the concepts of receptor mosaic (RM), and of horizontal and vertical molecular networks (HMNs, VMNs, respectively) are illustrated. To discuss some aspects of the functional organization of molecular networks, not only new data on protein-protein interactions but also the biochemical mechanism of cooperativity will be used. On this basis, some theoretical deductions can be drawn that allow a tentative classification of the RMs and the proposal of the extension of the concept of branching point introduced for enzymes to the possible switching role of some RMs in directing signals to various VMNs. Finally, the cooperativity phenomenon and the so-called symmetry rule will be used to introduce a proper mathematical approach that characterizes RMs as to their receptor composition, receptor topography, and order of receptor activation inside the RM. These new data on G protein-coupled receptors and molecular network organization indicate possible new approaches for drug development.Journal of Molecular Neuroscience 01/2005; 26(2-3):193-208. · 2.89 Impact Factor