Our ability to learn and remember information about our environment is thought to be underpinned by the process of synaptic plasticity. This means that during learning episodes, synapses are stimulated by specific patterns of activity and exposed to neuromodulators that lead to the induction of synaptic plasticity. Subsequently, plasticity is expressed either by the insertion or removal of postsynaptic neurotransmitter receptors or by changes in the amount of neurotransmitter released from the presynaptic terminal.
Research in our laboratory is focused on what regulates the induction of synaptic plasticity and the mechanisms underlying its expression. Currently we are studying,
1) The role of the neuromodulator acetylcholine in the hippocampus.
2) The patterns of activity that induce synaptic plasticity.
3) The regulation of neuronal excitability and the effect this has on the induction of synaptic plasticity.
4) The mechanisms underlying postsynaptic glutamate receptor trafficking.
This work is mainly performed using electrophysiological recordings from neurones in brain slices.
The role of acetylcholine in the hippocampus.
Acetylcholine has a major neuromodulatory input to the hippocampus and has been shown by us and others to increase neuronal excitability and facilitate the induction of synaptic plasticity (Isaac et al., 2009; Buchanan et al., 2010; Petrovic et al., 2012; Teles-Grilo Ruivo and Mellor, 2013). We aim to define how these effects are mediated and what the sum effect of acetylcholine is on the hippocampal network. Through collaborations with Lilly and GSK we aim to use this information to develop compounds to enhance memory encoding and consolidation in the hippocampus.
The neuronal activity patterns required for synaptic plasticity induction.
The hippocampus is believed to encode episodic memories (or memory for events) by the process of synaptic plasticity. However, the precise events that occur during learning to induce synaptic plasticity are currently unknown. Finding out what these are would represent a major advance in our understanding of how learning and memory are encoded. We investigate this problem by analysing the patterns of neuronal activity that induce synaptic plasticity and how these patterns relate to those that occur during learning episodes. We make use of hippocampal place cell recordings that occur in the hippocampus during spatial learning tasks. We can then replay these activity patterns into neurones within a brain slice to assess their ability to induce synaptic plasticity (Isaac et al., 2009; Mistry et al., 2010). Using artificial neuronal activity patterns we can also determine the critical activity patterns required to induce synaptic plasticity (Buchanan and Mellor, 2007; Buchanan and Mellor, 2010). We have also developed a computational model for synaptic plasticity based on the activation of postsynaptic NMDA receptors (Rackham et al., 2010)(MATLAB code available via link below). We are currently measuring postsynaptic spine Ca2+ transients in response to synaptic stimulation and have developed a denoising process to facilitate this (MATLAB code available via link below).
Regulation of neuronal excitability and its effect on synaptic plasticity.
Changes in neuronal excitability brought about by neuromodulators or long-term changes in ion channel properties alter the manner in which neurones process incoming information. We are interested in understanding how this occurs and how it affects the induction of synaptic plasticity. We have found a critical role for the neuromodulator acetylcholine in the induction of synaptic plasticity by naturally occurring activity patterns (Isaac et al., 2009) and we have shown that acetylcholine acts through muscarinic receptor inhibition of potassium channels (Buchanan et al., 2010; Petrovic et al., 2012). Previously, we also found a role for ion channel modulation in hippocampal granule cell excitability and plasticity (Mistry and Mellor, 2007). We are also interested in how kainate receptors and their plasticity can regulate neuronal excitability (Chamberlain et al., 2013).
Glutamate receptor trafficking.
In collaboration with Dr Jonathan Hanley we investigate the role of PICK-1 in AMPA receptor trafficking (Dixon et al., 2009; Nakamura et al., 2011; Dennis et al., 2011; Rocca et al., 2013) and with Prof Jeremy Henley we investigate the role of SUMOylation in kainate receptor trafficking (Martin et al, 2007; Konopacki et al., 2011; Chamberlain et al., 2012). We use genetic modifications of specific neurones within hippocampal slices to assess the role of these proteins in synaptic glutamate receptor expression.
Complexity Science MSc/PhD:
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