Activity dependent restructuring of synaptic inputs
Dr Inbal Israely, Champalimaud Center for the Unknown, Portugal
Brain circuits can be structurally rearranged with experience, and synaptic connections can grow and be eliminated even in adult brains.
Many of these changes are long lasting and require the synthesis of new proteins. We are interested in elucidating the learning rules which govern plasticity at individual inputs, both functionally and structurally. We previously demonstrated that spine growth can be cooperative in a protein synthesis dependent manner, and that the simultaneous potentiation of spines induces competition for plasticity, which results in bi-directional changes in spine volume.
The mechanisms which regulate spine shrinkage, however, remain unclear. We examine the structural correlates of a protein synthesis dependent form of synaptic depression, mediated by metabotropic glutamate receptors, and find that in response to the global induction of LTD, a majority of spines shrink or are eliminated. These effects can be observed up to 24 hours following plasticity, and require new protein synthesis. Interestingly, synaptic activity is also needed for spine shrinkage, although not NMDA receptor function. Finally, we use two-photon imaging and glutamate uncaging to stimulate and monitor plasticity at single spines. Therefore, we explore how different forms of activity influence synaptic structure and function, and how information is encoded in a circuit.
Deciphering biochemical information processing during plasticity at single synapses
Professor Haruhiko Bito, University of Tokyo Grad School of Medicine, Japan
The nervous system adapts to a fluctuating environment through activity-dependent modulation of neuronal properties such as synaptic plasticity. The direction and extent of such sustainable modulation is determined by the stimulus parameters, suggesting that the biochemical machineries that operate at synapses can readily compute the input information. Ca2+- and calmodulin-dependent kinase II (CaMKII) and calcineurin appear to play key roles in these processes. However, several important theoretical postulates underlying the role of CaMKII and calcineurin during synaptic plasticity—e.g. that CaMKII in spines functions as a high-frequency input detector or that calcineurin is uniquely activated by low-frequency stimulation—remain untested in living neurons. Furthermore, whether and how the information encoded in glutamate release rates at individual synapses can be reliably converted into biochemical activation patterns of these postsynaptic enzymes also remains unexplored. To address these questions, we developed a novel dual FRET imaging platform and recorded CaMKIIα and calcineurin activities in hippocampal neurons, while varying glutamate uncaging frequencies. Five Hz spine glutamate uncaging strongly stimulated calcineurin but not CaMKIIα, with little spine morphological change. In contrast, 20Hz spine glutamate uncaging which induced spine growth activated both CaMKIIα and calcineurin, with distinct spatiotemporal kinetics. Higher temporal resolution recording in the soma revealed that CaMKIIα activity summed supralinearly and sensed both higher frequency and input number, thus acting as an input frequency/number decoder. In contrast, calcineurin activity summated sublinearly with increasing input number and showed little frequency-dependence, thus functioning as an input number counter. Further analyses of the dual recording of Ca2+ transients and downstream enzyme activities revealed that this distinction in fact resulted from the differential decoding of Ca2+ amplitudes vs Ca2+ integrals by CaMKII and calcineurin, respectively. These results provide evidence that CaMKIIα and calcineurin are activated through distinct non-linear Ca2+ decoding mechanisms, and fine-tuned to unique bandwidths, thus computing distinct input variables in an asymmetric, rather than opposing manner. Deciphering critical rules underlying key enzymatic information processing at excitatory synapses enhance our understanding of the temporal and spatial dynamics of molecular memory events underlying synaptic plasticity and learning & memory.
Hebb’s Original Exemplar – plasticity in primary visual cortex enables the detection of novelty
Dr Sam Cooke, Howard Hughes Medical Institute, MIT, USA
The cerebral neocortex stores memory. Understanding how this storage occurs requires identification of simple forms of memory that rely upon plasticity within circumscribed areas. As Donald Hebb originally surmised, the primary sensory cortices are likely to be the most experimentally tractable due to their proximity to sensory input, and he therefore chose perceptual learning in primary visual cortex (V1) of the rodent as a central example to expound his theories of how the brain stores information. Here I revisit Hebb’s ideas to consider roles for homo-synaptic plasticity in the modification of vision and behaviour through experience. I will describe a form of visual learning in the mouse that is highly selective for stimulus orientation. The resulting memory, sometimes described as familiarity, is manifested as behavioural habituation and likely serves an important function throughout the animal kingdom, enabling organisms to devote cognition to novel elements of the environment that may carry threat or yield reward. During my talk I will describe results revealing that this form of learning is mediated by input-specific synaptic plasticity within V1 that shares many of the features of canonical long-term potentiation (LTP).
LTP-Induced Neural Network Reorganization: fMRI and electrophysiological evidences
Dr Santiago Canals, Instituo de Neurociencias, Consejo Superior de Investigaciones Científicas y Universidad Miguel Hernández
Encoding patterns of synaptic activity into a long-term memory requires molecular and physiological changes at the cellular level but also network interactions. While the cellular mechanisms linking synaptic plasticity to memory have been intensively studied, those regulating network interactions have received less attention. Combining high-resolution fMRI and in vivo electrophysiology we demonstrate a functional remodeling of long-range hippocampal networks induced by long-term potentiation of synaptic plasticity in the perforant pathway. We will present the results of our last experiments investigating the cellular mechanism underlying this synapse-to-network transformation.
Metaplasticity: changing the future of synaptic plasticity
Professor Cliff Abraham, University of Otago, New Zealand
Like memory, synaptic plasticity is regulated by many intrinsic and extrinsic variables that affect the neuronal "state". One variable increasingly realised to affect neuronal state is the history of activity in the relevant neural network. We have termed such regulation "metaplasticity". Metaplasticity mechanisms are varied, and likely serve diverse functions. They also range in extent from being synapse-specific to cell-wide. Cell-wide metaplasticity is of particular interest as it can subserve homeostatic control of plasticity thresholds, thereby helping to impart stability to neuronal activity and network function through prevention of runaway synaptic potentiation or depression. The need for such control has been reported in many computational models of plasticity, but experimental demonstrations of such effects are few. Recently we have shown that cell-wide metaplasticity can occur in hippocampal slices in a way that could mediate homeostatic control of synaptic efficacy. Surprisingly, investigations of its mechanisms have indicated a role for intercellular communication, including a contribution by astrocytes. These findings suggest the possibility that homeostatic metaplasticity mechanisms can function at the network level.
Supported by the New Zealand Marsden Fund, the Health Research Council and the Neurological Foundation of New Zealand.