Interneuron Diversity series: Fast in, fast out – temporal and spatial signal processing in hippocampal interneurons

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Abstract

The operation of neuronal networks crucially depends on a fast time course of signaling in inhibitory interneurons. Synapses that excite interneurons generate fast currents, owing to the expression of glutamate receptors of specific subunit composition. Interneurons generate brief action potentials in response to transient synaptic activation and discharge repetitively at very high frequencies during sustained stimulation. The ability to generate short-duration action potentials at high frequencies depends on the expression of specific voltage-gated K+ channels. Factors facilitating fast action potential initiation following synaptic excitation include depolarized interneuron resting potential, subthreshold conductances and active dendrites. Finally, GABA release at interneuron output synapses is rapid and highly synchronized, leading to a faster inhibition in postsynaptic interneurons than in principal cells. Thus, the expression of distinct transmitter receptors and voltage-gated ion channels ensures that interneurons operate with high speed and temporal precision.

Section snippets

Fast glutamate-mediated excitation of interneurons

The first step is the excitation of GABAergic interneurons at glutamatergic synapses (Figure 1). As at other excitatory synapses, glutamate preferentially activates AMPA-type glutamate receptors. However, at excitatory synapses on interneurons, the AMPA-receptor-mediated excitatory postsynaptic current (EPSC) rises and decays rapidly 14, 19, 20 (Figure 1c). AMPA-receptor-mediated EPSCs at mossy fiber–basket cell synapses of the dentate gyrus, at mossy fiber–stratum lucidum interneuron synapses

Spatiotemporal signal processing in interneuron dendrites

Synaptic integration, in addition to depending on the time course of the postsynaptic conductance, depends on the dendritic location of the synapse and the cable properties of the dendrite 33, 34. In different interneuron subtypes, electron microscopical analysis suggests that 70–90% of synapses are excitatory [35]. The total population of excitatory synapses appears to be distributed uniformly over the somatodendritic domain, with 95–97% of synapses terminating on dendrites 35, 36. However,

Tuning of resting membrane potential by neuromodulators

As first suggested by Eccles, interneurons are more excitable than principal cells [52]. More recent evidence suggests that this increased excitability is partly due to the relatively depolarized resting potential of interneurons, which sets them in a ready-to-fire mode. Both non-invasive cell-attached recordings 53, 54 and conventional whole-cell techniques 42, 43, 55 revealed that the resting potential of different interneuron subtypes (e.g. basket cells and stratum radiatum interneurons) is

Active conductances shape EPSPs and generate resonance behavior

Depending on both EPSP amplitude and resting potential, subthreshold active conductances will contribute to the high speed, reliability and temporal precision of EPSP–action potential coupling in interneurons (Figure 3). As in pyramidal neurons 73, 74, activation of Na+ channels amplifies subthreshold EPSPs in several interneuron subtypes 30, 36, 75. Unlike in pyramidal neurons, however, activation of voltage-gated K+ channels actively terminates EPSPs. This leads to EPSPs with largely

Molecular determinants of the fast-spiking phenotype

Mountcastle et al. [82] first described neocortical neurons with ‘thin spikes’ in extracellular recordings. McCormick et al. [83] identified cortical cells with brief action potentials as GABAergic neurons and showed that these could fire repetitively without accommodation at frequencies >200 Hz. However, subsequent analysis of different interneuron subtypes indicated that many, but not all, interneurons show this fast-spiking phenotype (Figure 5). Basket cells, hilar interneurons with axons

Active dendritic propagation of action potentials

In pyramidal neurons, EPSPs propagate from the dendrite to the soma and the axon initial segment, the primary site of integration and action potential initiation [102]. By contrast, interneurons can use a different signaling strategy (Figure 6). First, in some interneuron subtypes the axon emerges from a principal dendrite rather than the soma. Dendritic origin of the axon, first described in GABAergic neurons of the substantia nigra [103], has been reported for oriens alveus interneurons in

Synchronous GABA release at interneuron output synapses

Once initiated, interneuron action potentials propagate along the axon and trigger GABA release from inhibitory terminals (Figure 7). The reliability of impulse conduction in morphologically complex interneuron axons is unknown. However, both the high release probability at the basket cell–granule cell synapse in the dentate gyrus [111] and the reliability of action-potential-evoked Ca2+ signals in axons of cerebellar interneurons [112] suggest that conduction failures are rare. Kainate

Concluding remarks

In both hippocampal and neocortical microcircuits, GABAergic interneurons differ radically from glutamatergic principal cells. Some of the properties of interneurons are reminiscent of neurons in the auditory pathway, where temporal precision is crucial for sound localization. Remarkable similarities between interneurons and auditory neurons include the expression of special AMPA receptors mediating fast synaptic excitation, the rapid membrane time constant, and the expression of Kv3 channels

Acknowledgements

We thank Marlene Bartos, Jan Behrends, Michael Häusser, Manfred Heckmann, Chris McBain, Jean-Christophe Poncer, Greg Stuart and Imre Vida for reading previous versions of the manuscript. Work of the authors was supported by the Deutsche Forschungsgemeinschaft, the Alexander-von-Humboldt Foundation, the Human Frontiers Science Program Organization, INSERM, the National Institutes of Health (MH54671), and the Ministère de la Recherche

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