Molecular and structural determinants of plasticity in the cerebral cortex

The cerebral cortex is most highly developed in man. It gives us important abilities and attributes such as the ability to see, feel and hear the world around us and to remember and recognise these features. The cortex is also responsible for higher order cognitive abilities such as speech, planning, abstraction and imagination. One of the key properties of the neurons in the cerebral cortex is their ability to change their connections with one another in responses to lasting changes in the environment or in response to injury. This process is known as synaptic plasticity; ?synaptic? because synapses form the connections between neurons and ?plasticity? because once changed, the synapses stay in their new form until made to change again. Without synaptic plasticity the brain is unable to develop properly. Synaptic plasticity disorders can lead to mental retardation during development. Synaptic plasticity is also required for normal memory formation and is impaired in Alzheimer?s disease. During recovery from stroke, synaptic plasticity is required in order to reassign function among the cells that survive the injury. It is beneficial for us to understand the basic mechanisms of synaptic plasticity in order to envisage therapies for enhancing recovery from stroke, for increasing the ability to learn in mental retardation and increasing the ability to remember in Alzheimer?s disease. This set of studies aims to advance our understanding of synaptic plasticity by finding out the links between the early stages of plasticity that are at present reasonably well understood and the structural changes in plasticity that ensue that are not at all well understood. We will do this in a relatively simple area of cortex concerned with processing information from the tactile surface of the body known as the somatosensory cortex. We will directly observe physical changes in the connections between neurones using a specialised microscopy method that allows repeated viewing of the same neurons over days and weeks. We will use genetic mutations to understand the molecules controlling these physical changes. We will study the effect of sensory experience on the connections in the cortex, which is of direct relevance to physiotherapy used during rehabilitation from stroke. Results from these studies should ultimately provide us with methods for improving recovery from stroke and potential therapies for learning and memory disorders.

The aim of this study is to understand the connection between early synaptic plasticity events such as LTP and LTD, which can be described at the cellular level and receptive field plasticity such as experience-dependent potentiation and depression that can be described at the systems level. Our hypothesis is that structural plasticity occurring at the level of spines and presynaptic axons is controlled by the same factors that control LTP and LTD, thereby explaining why similar factors are critical for LTP and experience-dependent potentiation and LTD and experience-dependent depression. To test this idea we will capitalise on our recent findings that GluR1 knockouts show potentiation but not depression and conversely that CaMKII-t286a point mutants show depression but not potentiation to identify the corresponding components of spine plasticity in vivo using 2-photon imaging. We will also test whether signalling pathways that lead to LTP with different pre- and post-synaptic loci in the neocortex also have different pre- and post-synaptic structural sites of action. To test this we will use GluR1 knockouts that show predominantly presynaptic LTP and alphaNOS1 knockout that show predominantly post-synaptic plasticity and compare the dynamics and nature of their spine and axon plasticity. In order to link these new structural plasticity studies with the existing literature on LTP and receptive field plasticity, these experiments will be performed on layer II/III cells electroporated with GFP rather than the layer V cells that are normally studied in structural plasticity experiments. This is a vital distinction because we have recently found differences in the mechanisms of plasticity in the two sets of layers. Finally, we will characterise the receptive field plasticity of layer V cells in order to link it to the existing literature on structural plasticity. We will study the source of the experience dependent depression and LTD mechanism in layer V that is not shared with layer II/III cells. Because of the diversity of layer V pyramidal cells we will distinguish between plasticity of sublaminae Va and Vb and between septal/barrel subdivisions and between intrinsic burster versus regular spiking cells.