Molecular networks of memory maintenance and dysfunction in neural circuits

About This Grant

How networks of molecules persistently modify neuronal ensembles to store long-term memory is a fundamental question in neuroscience, relevant for disorders characterized by memory-like dysfunction of brain circuits. Whereas transient second messengers activate many kinases to briefly modify synaptic strength, the second messenger-independent, atypical PKC isoform, PKMz, is persistently active. Strong stimulation of synapses increases cellular PKMz through new synthesis; however, the kinase’s action maintains potentiation only at activated synapses. Our initial work on how PKMz selectively targets active synapses reveals PKMz does not act alone, but interacts continually with other molecules to maintain potentiation of specific synaptic connections. The postsynaptic scaffolding protein, KIBRA, genetically linked to human memory, forms persistent complexes with PKMz in LTP. Blocking their interaction reverses established LTP, without affecting unstimulated synaptic strength. The antagonists disrupt 1-month-old spatial memory, during which PKMz has been degraded and resynthesized. Thus, KIBRA acts as a persistent synaptic tag, anchoring PKMz to maintain LTP and memory despite protein turnover. PKCi/l compensates for PKMz loss in z-knockout mice and is also anchored at active synapses. Understanding this persistent synaptic tagging requires elucidating molecular networks that form and maintain potentiation at active synapses, and how this tagging modifies neuronal ensembles to store memory. Thus, Aim 1 is to identify the molecules establishing KIBRA-PKMz coupling at activated synapses. Multiple proteins interact with KIBRA, including the actin-associated protein dendrin and protein interacting with C-kinase (PICK1) that also binds both PKMz and AMPARs. Actin filaments and postsynaptic AMPARs increase in early-LTP. We will test whether dendrin and PICK1, together with other molecules identified by proteomic screening, accumulate KIBRA in early-LTP, which then anchors PKMz in establishing late-LTP. Aim 2 examines molecular networks maintaining KIBRA-PKMz complexes in LTP and memory. KIBRA stabilizes PKMz, and we will test if this stabilization and the persistent action of PKMz to strengthen synapses act in feedback pathways to perpetuate KIBRA-tagging in maintenance. We will use dual-eGRASP that persistently labels with fluorescent markers synapses activated in learning to examine KIBRA-PKMz coupling in activated synapses during spatial memory. Aim 3 investigates how KIBRA-PKMz persistent synaptic tagging expresses memory through modifications of place cell ensembles. Standard measures of place cell fields change only modestly as animals learn spatial information. Our recent optical recordings of hundreds of place cells reveal subpopulations of cells that form and maintain new cofiring relationships during spatial memory. Initial data show decoupling KIBRA-PKMz erases memory, and we will test if memory-related place cell ensembles and the spatial information they encode are also disrupted. Our 3 Aims will elucidate the molecular networks crucial for persistent synaptic tagging and so establish a basis for understanding disorders of memory.