Local circuit connections of interneurones in CA1 of the rat hippocampus: Dual/triple whole-cell and sharp recordings

There are many cells in the brain (109), which are wired to form specialized circuits. These circuits have many functions ranging from; perception, movement and memory. How the circuits perform their tasks is largely due to the type of receptors they posses, their morphological structure and who they are wired with. This complex wiring of neurones makes the brain the most complex organ however; the way it works can be simplified into two opposing forces; excitation and inhibition. Neurones which work via chemical synapses are excited by excitatory pyramidal cells using neurotransmitter glutamate and are inhibited by inhibitory interneurones releasing the neurotransmitter, GABA that acts on GABA receptors. Under or over activity of these 2 opposing forces have been implicated in neurodegenerative (e.g. epilepsy and Parkinson?s disease) and psychiatric diseases (e.g. anxiety and schizophrenia). The proposed research is to provide a better understanding of how the homeostatic balance of inhibition and excitation is achieved.
80% of cells in cortical regions consist of the pyramidal cell family while inhibitory interneurones consist of 6-7% of cells in cortical regions. Interneurones fall into different sub families, which are diverse in their morphology, neurochemistry, electrophysiological properties and the type of GABA receptors they posses. The interneurones make synapses with pyramidal cells and other interneurones to regulate and fine tune pyramidal cell activity, thus preventing over excitability of the network. This study is very important since not only will it provide valuable information on interneurone physiology, pharmacology and morphology but will also provide insight on neuronal subtypes which may be selectively affected in a particular disease states. The outcome of this research has direct relevance to human neuropathology, since it will allow us to design drugs to target specific pathways in the brain to treat neurological disorders, including depression and anxiety, which impact significantly on UK citizens, i.e. 1 in 4 adults may experience a mental health problem in any given year. Depression alone is thought to be the second most costly illness worldwide (Murray and Lopez, 1996) by year 2020, representing the biggest global economic health burden after heart disease. The treatment for such disorders include benzodiazepines, barbiturates, which act through GABAA neurotransmitter receptors, making the GABAA receptor a prime target for the development of new drugs and improved selectivity of existing ones.

The activity of interneurones is fundamental to cortical function. They provide a homeostatic balance between excitation and inhibition, controlling dendritic electrogenesis and spike generation in pyramidal cells as well as setting and maintaining oscillatory rhythms. Anatomical studies described classes of interneurones that make synaptic contacts on specific domain of pyramidal cells as well as other interneurones, some being specialized to innervate interneurones only. Although synaptic interactions between pyramidal cells and interneurones are becoming well documented, less is known about the synaptic interactions between interneurones physiologically and pharmacologically. Also, evidence for the selective insertion of presynaptic receptors at specific synapses is growing; however, how these receptors variously modulate inhibition still requires detailed investigation. The aim of the present study is to investigate the physiology and pharmacology of local circuit connections between interneurones using dual/triple whole-cell and sharp recordings combined with immunofluorescence and biocytin labelling in acute slices of the CA1 region of rat hippocampus.
The outcome of this study will enhance our understanding of cortical network behaviour by determining the various ways inhibitory interneurones communicate with each other and how excitation is governed at a unitary level.