Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory

Jakovcevski et al. suggest a possible molecular role for prefrontal methyltransferases in working memory, emotion and cognition. Such an interesting observation throws an unexpected bridge between topology, molecular assemblies and brain function. Methyltransferases are among the rare enzymes exhibiting the weird property of... a knot in their backbone. In other words, they are proteins with structures that do not disentangle completely after being pulled from both ends (Virnau et al., 2011). A knot is indeed the embedding of a closed line in the 3D space and cannot be reduced to a simple circle by a continuous deformation (Wu, 1992). The knot theory arises from topology and provides tools for cataloguing different types of knots, for possibly transforming one into another via a deformation of 3D space upon itself and for summing different knots in assemblages equipped with commutative and associative properties (Cromwell, 2004). In turn, the recently developed concept of "supramolecular chemistry" suggests that complex chemical entities can be reversibly constructed from molecular components bound together by labile non-covalent interactions (Lehn, 2007). The novel idea involves the storage of information at the molecular level and its retrieval, transfer and processing at the supramolecular level, via transitory processes that are self-organized, self-assembled and dynamic (Taylor and Ehrenreich, 2014). Incorporating such different perspectives appears to be particularly relevant for understanding how the brain does represent the stimuli coming from the environment and the internally directed, spontaneous deliberate self-generated thought (Andrews-Hanna et al., 2014). Recent findings suggest that nervous structures could process information through topological, other than spatial, mechanisms: for example, it is believed that hippocampal place cells create a topological template to represent spatial information (Dabanghian et al., 2014). Further, structures quite different from spikes, such as macromolecular assemblies, may play a role in information processing in nervous system: we do not yet understand to what extent the diffusion and biophysical cues, such as the mechanical properties of the extracellular matrix (Sur et al., 2013), have to be taken into account when talking about the brain function. In conclusion, the thoughts could be metaphorically compared with open strings made of proteins and/or supramolecular assemblies, a sort of random-walks wandering around in the viscous fluid of the nervous melieu. The entanglement of their extremities may give rise to reversible or irreversible topological knots, respectively standing for labile or enduring perceptions and memories.

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Conflict of Interest:

None declared