Regulation of plateau potentials by dendritically targeted inhibitory synaptic transmission.

Experience-dependent memory is the foundation on which we make all our decisions. Reliable memory encoding is therefore essential for good decision making and our mental health. But what determines the durability of memories and how are they protected from interference by subsequent events?

Our brains are not like computers which reliably transcribe all information faithfully and equally - we have a much greater capacity for flexibility. But how do we balance the needs for flexibility and adaptation with reliability and stability?

Memory representations in the brain are thought to be encoded in the strength of connections (synapses) between neurons creating assemblies where each neuron represents a distinct aspect of the memory. An excellent example of this are place cells of the hippocampus which each represent one specific location but can group together by strengthening their synaptic connections into assemblies that provide a representation or memory of the whole environment.

When we experience a new environment the place cell assemblies must reorganise to form a new representation where each place cell may now "re-map" to a different location. The hippocampus is therefore an excellent system to study the flexibility and stability of memory representations.

The biological substrate for memory formation is therefore modifications in the strength of synaptic connections. This plasticity enables the reorganisation of cell assemblies. Synaptic plasticity is triggered by the influx of calcium ions across the synaptic membrane through proteins called NMDA receptors.

If multiple excitatory synaptic inputs are activated simultaneous, a plateau potential is generated which is a long-lasting activation of NMDA receptors and calcium influx. These plateau potentials are known to be important in triggering synaptic plasticity to encode new aspects of our environment into place cells.

We propose that plateau potentials are controlled by inhibition provided by a specialised subtype of inhibitory neuron termed an OLM interneuron. These inhibitory cells can counteract excitatory synaptic input and are therefore perfectly positioned to regulate plateau potentials and the resulting synaptic plasticity and memory formation. Furthermore, we propose that OLM adaptation is important for creating stable memory representations.

In this BBSRC project, we will test the hypothesis that OLM interneurons can control when new place cells can incorporate new information by regulating plateau potentials and synaptic plasticity. To do this we will fill neurons with dyes that fluoresce when calcium ions are present and measure whether a synapse has strengthened or weakened by recording electrical activity from the neurons.

We will do this while activating OLM interneurons to test how these cells regulate neuronal calcium and synapse strength. We will then record place cells in the hippocampus and investigate if OLM inputs can keep a place cell stable and prevent new information from destabilising previously encoded representations of the world.

This work is important because it will lead to a wealth of new information about place cells and synaptic plasticity. Dysfunctional synaptic plasticity is thought to underlie the altered neuronal activity in several brain diseases, such as Alzheimer's disease and schizophrenia. Therefore, the mechanisms that we will study in this research will add to our knowledge about these debilitating diseases and may contribute to developing novel therapies.