Importance of long-range inhibitory connections in hippocampal network oscillations

Hippocampus is the brain structure crucial for memory and learning processes. In abnormal condition it is the focus of the most common epilepsy in adults called temporal lobe epilepsy. Proper function of the hippocampus requires a well-orchestrated activity of neurons. The synchronization in the neural network is maintained by inhibitory neurons, which make up only 10% of the cell population. As demonstrated before, different inhibitory cells have various functions in the network activity. Locally acting neurons are the best studied in the inhibitory cell group because the commonly utilized brain slicing method relatively marginally alters the connectivity of this type of cells. However, inhibitory neurons with long axonal arborization eluded researcher until today because the investigation requires intact brain preparation. I propose that long projection inhibitory neurons have a critical role in the hippocampal function and organization. This cell type can synchronize neural activity in large populations of cells through its extensive axonal arborization. I propose to investigate the functional significance of this special type of neuron in using a wide variety of research tools. A better understanding of the normal and abnormal brain function may in time provide new and more specific treatments for epilepsies.

The spread of excitation in the hippocampus is controlled by inhibitory neurons. Various inhibitory cell types are responsible for shaping behaviorally dependent network activities such as theta and sharp-wave associated ripple oscillations. Based on the extent of axonal arborization interneurons are divided into local circuit and long-projection cells. Long-projection neurons exert a global effect on their target, but the function of these cells is unknown.

The working hypotheses are:
-Long-projection inhibitory neurons belong to a well-defined subpopulation of cells;
-These interneurons play a crucial role in ripple oscillation;
-Synchronization of ripple events between the two hippocampi is maintained by long-range inhibitory cells.

Using a combination of in vivo cellular electrophysiology, multichannel recording, immunohistochemistry, electron microscopy and molecular biology, we investigate: 1) the proportion and the axonal arborization of long-projection neurons; 2) the synaptic targets of these neurons; 3) the axonal trajectory of the long-projection neurons to the contralateral side; 4) the firing pattern of these neurons in different network oscillations; 5) the effect of selective elimination of long-projection neurons in intra- and interhippocamapal synchronization.

Thorough knowledge of inhibitory neuronal network is essential for understanding the involvement of the hippocampus in memory formation, ischemic damage, and temporal lobe epilepsy.