P210 Biochemically detailed modelling of cortical synaptic plasticity: the effects of timing of neuromodulatory inputs on LTP/LTD
Tuomo Mäki-Marttunen*1, Verónica Mäki-Marttunen2
1Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland 2NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Norway
*Email: tuomo.maki-marttunen@tuni.fi Introduction
Synaptic plasticity is a time-sensitive phenomenon. The timing of action potentials in pre- and postsynaptic neurons is well known to influence plasticity outcomes through Hebbian spike-timing-dependent plasticity mechanisms. It is also known that the neuromodulatory state of the neuron strongly affects plasticity [1]. However, it is not fully understood how the timing of neuromodulatory inputs to the cells affects plasticity outcomes [2]. Neuromodulatory activity is important for learning and memory consolidation [3], and thus, understanding how neuromodulatory inputs interact with neuronal activity will allow to gain a deeper view of how brain plasticity is regulated at a higher level [4-6]. Methods Here, we use a multi-pathway model of synaptic plasticity in the cortex [7-8] to study the interaction between the timing of neuromodulatory and Ca2+inputs to the postsynaptic spine in shaping synaptic plasticity. We investigate how different forms of plasticity are affected by the exact timing of neuromodulatory inputs from the locus coeruleus, which is the main source of norepinephrine (NE) in the mammalian brain, relative to high-frequency Ca2+inputs. Results We show that when Ca2+inputs are followed by NE inputs, strong LTP can be observed, whereas LTD occurs when Ca2+inputs followed NE inputs. This effect is caused by a difference in the amount of cAMP produced and PKA activated between the two stimulation protocols: the Ca2+-> NE protocol induces strong PKA activation and GluR1 exocytosis, while the NE -> Ca2+protocol yields much smaller PKA activation. Discussion Animal studies suggest that the timing of fast activation of neuromodulatory centers is important [9] and may play a role in the oscillatory processes that underlie memory consolidation during sleep [10]. In addition, recent studies suggest that neuromodulatory activity at slower time scales during sleep presents a timed relation with oscillatory events underlying memory consolidation [11-12]. Our results suggest that a timely activation of locus coeruleus within a wave of brain activity can be crucial for the plasticity outcome, which can have important implications for our understanding of learning and memory consolidation.
Acknowledgements Funding: Academy of Finland (330776, 358049). The authors also wish to acknowledge CSC Finland (project 2003397) for computational resources. References
