Exploring gap junction location and density in electrically coupled hippocampal oriens interneurons
Introduction
Interneuronal networks are thought to play an important role in shaping the population field rhythms measured during exploration (theta rhythms) and memory consolidation (sharp waves and ripples) in the hippocampus. There is growing evidence that GABAergic interneuronal networks in the cortex and hippocampus are connected by both electrical and chemical synapses. Electrical synapses are specialized sites where gap-junctional channels bridge the membrane of adjacent cells. Gap junctions (GJs) allow direct transmission of charged particles and small molecules between cells and are thought to mediate synchronous firing in connected neurons. They are found between many neurons in the mammalian central nervous system [2].
Anatomical studies show that basket cells, an interneuron subtype, form dendritic GJs with other basket cells [3], [4]. Modeling studies show that various network patterns including synchronous and phase-locked patterns occur depending on GJ location and strength [1], [7], [10]. Recent electrophysiological studies indicate that electrical coupling exists between oriens interneurons in the CA1 region of the hippocampus [12]. Full spikes in one cell failed to generate spikes in the connected cell, but rather generated spikelets of amplitudes ranging from 0.6 to 1.1 mV and delays ranging from 3 to 5 ms, indicating weak coupling between the cells. Oriens interneuron subtypes are known to have a high density of sodium and potassium channels on their dendrites allowing them to produce strong back-propagating action potentials [8]. Given that the experimental work of Zhang et al. [12] indicates that oriens interneurons are only weakly coupled, we aim to quantify what this might mean. We use our previously published multi-compartment model of an oriens interneuron [9] and explore the possible location and strength of GJs between two oriens interneurons. In order for the simulated spikelets to fall within the experimentally determined ranges we find that GJs must be located between 150–200 μm from the soma with a GJ strength of 500–800 pS.
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Model and methods
Our model interneuron [9], created using the software NEURON [6], incorporates experimentally derived values for ion channel densities and kinetics, and can reproduce several key properties such as current–frequency relationships and action potential initiation sites. Ion channels included in the model interneuron are the traditional Hodgkin–Huxley (HH) sodium (INa) and delayed-rectifier potassium (IK) channels, the transient potassium channel (IA), the hyperpolarization-activated channel (Ih)
Results
Using the isolated juvenile (7–14 days) mouse whole hippocampus preparation, Zhang et al. [12] performed dual whole cell recordings from stratum oriens interneurons under infrared microscopy. With one cell hyperpolarized to −65 mV to minimize spontaneous firing, the other cell was allowed to spontaneously fire or was injected with current to evoke action potentials. Of the total paired recordings, ∼12–18% (depending on the orientation of the electrodes to the hippocampus) were found to be
Discussion
Although there is both electrophysiological and pharmacological evidence that a portion of oriens interneurons are connected by GJs, the location and strength of the coupling remains difficult to determine experimentally. However, using multi-compartment models of oriens interneurons we can make specific predictions on the location and strength of these gap junctional connections based on spikelet amplitude, shape and delay. Several cautionary points should be made at this time. Our
Acknowledgements
This work is supported by the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), and an Ontario Graduate Scholarship (OGS).
Fernanda Saraga is currently completing her Ph.D. at the University of Toronto. She graduated from the University of Toronto (B.Sc.—Physics and M.Sc.—Physiology). She is interested in creating computational models of inhibitory interneurons to understand their complex role in signal generation.
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Fernanda Saraga is currently completing her Ph.D. at the University of Toronto. She graduated from the University of Toronto (B.Sc.—Physics and M.Sc.—Physiology). She is interested in creating computational models of inhibitory interneurons to understand their complex role in signal generation.
Dr. Liang Zhang is a cellular neurophysiologist and his research focuses on cellular mechanisms of hippocampal network activities. His lab has established novel in vitro hippocampal preparations (whole hippocampal isolate and thick slice) from adult mice and has characterized intrinsic hippocampal GABAergic rhythms and in vitro hippocampal sharp waves.
Dr. Peter Carlen is a Neurologist and Senior Scientist at the Toronto Western Research Institute. He is also a professor in the Departments of Medicine (Neurology) and Physiology of the University of Toronto. His main research interests are mechanisms of neural synchrony and entrainment (epilepsy, movement disorders), neuroprotection and CNS aging.
Dr. Frances Skinner is a Senior Scientist in the Toronto Western Research Institute, University Health Network, with appointments in Medicine (Neurology), Physiology and Biomedical Engineering at the University of Toronto. She graduated from the University of Waterloo (B.Math.) and Toronto (M.A.Sc., Ph.D.) and did 4 years of postdoctoral work in Boston and California. In general, she enjoys collaborative work and is interested in cellular-based mechanisms underlying neuronal network dynamics.