The neurobiological bases of memory formation: from physiological conditions to psychopathology

Abstract

The formation of long-term memories is a function necessary for an adaptive survival. In the last two decades, great progress has been made in the understanding of the biological bases of memory formation. The identification of mechanisms necessary for memory consolidation and reconsolidation, the processes by which the posttraining and postretrieval fragile memory traces become stronger and insensitive to disruption, has indicated new approaches for investigating and treating psychopathologies. In this review, we will discuss some key biological mechanisms found to be critical for memory consolidation and strengthening, the role/s and mechanisms of memory reconsolidation, and how the interference with consolidation and/or reconsolidation can modulate the retention and/or storage of memories that are linked to psychopathologies.

Figure 1. Schematic representation of learning induced changes in the hippocampus through the GR-BDNF-TrkB pathway

Activated GRs rapidly enhance the translation of Arc and may influence trafficking of TrkB to the membrane surface and/or BDNF release. BDNF binding to its receptor TrkB leads to its phosphorylation, which results in the activation of ERK1/2, Akt and PLCγ. In parallel, activated GRs, via transcription-dependent mechanisms, also rapidly lead to CaMKIIα phosphorylation. The activation of ERK1/2, Akt, PLCγ, and CaMKIIα pathways independently or in concert can converge in CREB phosphorylation, which leads to the synthesis of BDNF. The newly synthesized BDNF sustains the activation of the pathways and results in persistent phosphorylation of CREB, CaMKIIα, and a downstream pre-synaptic target of CaMKIIα, phosopho-synapsin-1. Thus, GR activation recruits pre- and post-synaptic mechanisms to mediate memory consolidation [41]. Abbreviations: GR, glucocorticoid receptor; TrkB, tropomyosin-related kinase B receptor; BDNF, brain-derived neurotrophic factor; CaMKIIα, Calcium/calmodulin-dependent protein kinase α; CREB, cAMP response element binding protein; ERK, extracellular signal regulated kinases; Akt, protein kinase B; PLCγ, phospholipase Cγ; Arc, activity regulated cytoskeletal-associated protein; GluA1, AMPA receptor subunit A1; DAG, diacylglycerol; IP3, inositol triphosphate. Figure adapted from Finsterwald and Alberini (2013) [45].