Review
Glutamatergic synapses onto hippocampal interneurons: precision timing without lasting plasticity

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Abstract

In the hippocampal formation GABAergic inhibitory interneurons have a major role in the synchronization of neuronal activity and are involved in the generation of large-scale network oscillations. Thus, interneurons function as a ‘clock’ that dictates when principal cells fire during suprathreshold excitatory drive. Interneurons receive strong excitatory innervation from glutamatergic neurons and it has been much debated whether these synapses show mechanisms of long-term plasticity similar to those found at principal-cell synapses. Recent findings support the lack of conventional forms of LTP and LTD in most interneurons, partly owing to the distinct anatomical and neurochemical features of interneuronal excitatory synapses. The uncommon properties of excitatory synapses on interneurons might be required for their functioning as accurate and reliable neuronal oscillators.

Section snippets

Mechanisms of short-term plasticity

In cortical and hippocampal circuits, repetitive activation of afferents either progressively increases (facilitation) or decreases (depression) the amplitudes of excitatory synaptic events. Synapses can, therefore, be ‘facilitating’ or ‘depressing’ depending on whether subsequent excitatory events potentiate or depress, respectively. The depression or facilitation observed at a given synapse appears to be dictated in part by the target neuron9, 10. Excitatory transmission at hippocampal

Long-term postsynaptic plasticity

In the hippocampal formation, high-frequency stimulation of Schaffer collaterals that synapse with CA1 pyramidal cells induces LTP (Ref. 17). In contrast, after prolonged lower-frequency stimulation (∼1 Hz) pyramidal neurons express LTD (Ref. 18). In general, LTP and LTD in pyramidal neurons are homosynaptic, that is, only the activated synapses are potentiated or depressed, while the strength of transmission at inactive synapses remains unchanged. Although activity-dependent modifications of

The neurochemical basis of the lack of postsynaptic NMDA-receptor-dependent plasticity

Postsynaptic forms of LTP and LTD are dependent on Ca2+-signaling cascades, most importantly on two key enzymes, the Ser/Thr phosphatase 2B [or calcineurin (CN)], and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Both the kinase and the phosphatase are activated by Ca2+ and calmodulin, and whether the process favors the direction of phosphorylation or dephosphorylation appears to depend on the magnitude and time course of the cytosolic rise in Ca2+ concentration (Fig. 2B). Large

Structural correlates for a lack of postsynaptic NMDA-receptor-dependent synaptic plasticity

In principal neurons, the majority of excitatory glutamatergic synapses terminate on dendritic spines. These structures have often been implicated in postsynaptic LTP or compartmentalization of free cytosolic Ca2+. The hypothesis that memory might be stored in the shape of dendritic spines was first suggested by Rall and Rinzel in 1971 (Ref. 40). They proposed that changes in the dimensions of the spine neck and, consequently, its electrical resistance would influence the efficacy of synapses

A lack of presynaptic forms of synaptic plasticity.

Ramón y Cajal noted a unique feature of mossy-fiber axons: unlike any other cortical principal cell, granule cells have more than one terminal type along their axons56. Single granule-cell axons have specialized terminals, which include large mossy-fiber boutons, small en passant nerve terminals and filopodial extensions of the mossy-fiber boutons. The interneuron targets of granule cells are innervated preferentially by filopodial extensions and small en passant terminals54 (Fig. 4., Fig. 5).

Relevance to the interneuronal clockwork

Our present understanding of the anatomy and physiology of interneurons is consistent with these cells having a role that is much more complex than just a simple inhibition. The properties of the synaptic excitation of GABAergic cells, as well as the synaptic interactions between the interneurons themselves are thought to underlie the coherent oscillations of large neuronal networks, especially those in the 40 Hz (γ) range58 that are implicated in higher cognitive functions59, 60. In this

Concluding remarks

As discussed in this article, there are distinct anatomical and neurochemical features of interneuronal excitatory synapses that are consistent with the conspicuous unwillingness of these synapses to undergo lasting potentiation in the adult brain. Some, but not all, interneurons undergo indirect, for example, passively propagated, forms of long-term plasticity that can influence the properties of their target networks22. Unique forms of excitatory synaptic plasticity such as iLTD have,

Acknowledgements

The authors thank K. Toth, G. Maccaferri, M. Fleck, L. Ascady and A. Sı̀k for helpful discussion and for contributing figures from their original papers.

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