Role of the CA2 region in the hippocampal circuitry

The hippocampus is a relatively small brain area, but necessary for the acquisition of specific types of new knowledge, a form of memory called declarative memory. The normal, highly structured flow of information through this structure is essential for memory acquisition, for the processing of spatial information and for navigation. This flow and the processing of information are dependent on the proper wiring of the connections between nerve cells, or neurones, in the different regions of the hippocampus. Increasing clinical evidence links abnormalities in certain types of neurones with the pathology of specific psychiatric and neurological disorders. Although devastating to those affected and their families, these diseases do not typically result from global and dramatic changes in all types of nerve cells throughout the brain, but from relatively subtle alterations in the numbers, structure or connections made by certain subtypes. This project focusses on a region of the hippocampus, the CA2 region, that is uniquely resistant to damage in temporal lobe epilepsy, but which demonstrates abnormalities early in the onset of schizophrenia and in bipolar disorder (sometimes known as manic depressive illness). These abnormalities involve 'inhibitory interneurones', nerve cells that control and coordinate the flow of information and the components of an experience that we recognise as novel and/or relevant to our behaviour and which we then retain.

The CA2 region of the hippocampus is a distinct and unique region that has been little studied to date, but may nevertheless play an important role in hippocampal circuitry. CA2 receives direct inputs from the amygdala and entorhinal cortex and can relay this activity to CA1 in vivo, independently of the activation of the trisynaptic loop and the CA3 region. It is the only CA that receives inputs from the supramammillary body of the hypothalamus suggesting an important role in the generation of theta rhythms. CA2 is particularly resistant to cell death in temporal lobe epilepsy, but, early in the onset of schizophrenia and bipolar disorders the number of CA2 interneurones is dramatically reduced. We have recently demonstrated that CA2 interneurones in stratum pyramidale and their local synaptic connections differ strikingly from those in other CA regions. Of particular interest are the adapting firing patterns and pronounced sag in voltage responses to hyperpolarizing current injection displayed by CA2 interneurones containing parvalbumin and the axonal and dendritic arbours of several subclasses that ramify, in an apparently highly organised way, in CA1 and/or CA3. To increase our understanding of the position that this interesting region occupies in the hippocampal circuit, this study will characterise further CA2 interneuronal subclasses and their synaptic connections across CA-subfields. Of particular interest will be the behaviour of these neurones and the efficacy of their connections during network oscillations in the gamma and theta ranges.