Elsevier

Neuropharmacology

Volume 63, Issue 3, September 2012, Pages 486-493
Neuropharmacology

mGlu1α-dependent recruitment of excitatory GABAergic input to neocortical Cajal-Retzius cells

https://doi.org/10.1016/j.neuropharm.2012.04.025Get rights and content

Abstract

Cajal-Retzius cells are thought to play an important role for cortical development, and receive primarily spontaneous GABAergic input mediated by GABAA receptors. However, neither the effects of synaptically-released GABA on their excitability nor the cellular source(s) of spontaneous GABAergic currents have been yet determined. By directly recording electrophysiological responses from identified Cajal-Retzius cells of the CXCR4-EGFP mouse, we show that GABAergic input can trigger supra-threshold responses, and that the pharmacological activation of mGlu1α receptors with the group I agonist DHPG powerfully increases the frequency of spontaneous GABAergic currents. These effects appeared mediated by a network mechanism, because responses to DHPG were completely prevented both by surgical disconnection of layer I from lower layers and by exposure of slices to TTX.

We propose that the cellular source underlying the observed effect of DHPG are layer I-targeting Martinotti-like interneurons, which we show express functional group I mGluRs and respond to DHPG with supra-threshold depolarization already at early developmental stages.

In conclusion, our work suggests that conditions of enhanced glutamate release may be critical at early developmental stages for the recruitment of an mGlu1α-dependent micro-circuit, which then leads to the activation of Cajal-Retzius cells.

Highlights

► Spontaneous synaptic currents in Cajal-Retzius cells (CRs) are GABAergic. ► The frequency of these currents is massively increased by mGlu1α activation. ► This effect requires firing in cortical layers below layer I. ► DHPG triggers firing in layer II/III Martinotti interneurons (Ms). ► Ms of layer II/III are proposed to be a critical source of synaptic input to CRs.

Introduction

The embryonic marginal zone/postnatal layer I has been suggested to play a critical role in orchestrating the development of the neocortex (Marín-Padilla, 1998). In fact, after completing their radial migration, developing pyramidal neurons first make synaptic contacts with the marginal zone/layer I (Ramón y Cajal, 1904; Marín-Padilla and Marín-Padilla, 1982), and then are displaced toward deeper layers by newly arrived migrating cells, thus generating an inside-out pattern of cortical development (Angevine and Sidman, 1961). Therefore, all pyramidal cells seem to receive progressively, as they mature, the same kind of information from layer I. However, the detailed functions performed by the micro-circuitry operating within the marginal zone/layer I are not completely understood.

The principal neuron of the marginal zone/layer I is the Cajal-Retzius cell (reviewed by Soriano and Del Río, 2005), which has been the subject of numerous studies as a cellular source of the glycoprotein reelin (Tissir and Goffinet, 2003), which is essential for several functions ranging from the correct organization of cortical layers (D'Arcangelo et al., 1995), to the maturation of dendritic arbors (via different signaling pathways, see Niu et al., 2004, Niu et al., 2008; and Chameau et al., 2009) and their synaptic channels (Qiu and Weeber, 2007; Campo et al., 2009). Cajal-Retzius cells appear spontaneously active both at embryonic and postnatal stages. In fact, spontaneous calcium transients in Cajal-Retzius cells have been found to be synchronous in correlated networks including other Cajal-Retzius cells and/or different types of local neurons (Schwartz et al., 1998; Aguiló et al., 1999). This pattern of activity has been suggested to play computational roles, which have been postulated to be important for the development of the cortex. Intriguingly, several studies have indicated that Cajal-Retzius cells receive predominant, if not exclusive, spontaneous excitatory synaptic input mediated by GABAA receptors (Kilb and Luhmann, 2001; Soda et al., 2003). Synchronized calcium oscillations are sensitive both to tetrodotoxin, which blocks axonal conduction (Narahashi et al., 1964), and to bicuculline, which blocks GABAA receptors (Curtis et al., 1970). Thus, GABAergic input to Cajal-Retzius cells of the marginal zone/layer I could play a critical role for the recruitment of assemblies of Cajal-Retzius cells involved in this type of spontaneous activity.

Various types of GABAergic fibers have been shown to target the developing layer I: axons of local interneurons (Hestrin and Armstrong, 1996; Zhou and Hablitz, 1996; Marín-Padilla, 2011a, Marín-Padilla, 2011b; Wozny and Williams, 2011), subplate cells (Friauf et al., 1990; Myakhar et al., 2011; Marín-Padilla, 2011a, Marín-Padilla, 2011b) and thalamic zona incerta neurons (Lin et al., 1990). Paired recording between layer I interneurons and Cajal-Retzius cells have revealed a very low degree of connectivity, suggesting that GABAergic pathways originating from lower layers may provide a more significant input (Soda et al., 2003).

Here, we unravel a massive source of GABAergic input to Cajal-Retzius cells, which is powerfully activated by pharmacological agonists of group I metabotropic glutamate receptors (mGluRs) via mGlu1α. We propose that activation of GABAergic interneurons expressing mGlu1α, possibly Martinotti cells, plays an important role in generating synchronous network activity in Cajal-Retzius cells of the developing layer I, and hence, in contributing to their computational functions.

Section snippets

Slice preparation

All animal experiments were carried out in accordance with the National Institutes of Health guide for the care and use of Laboratory animals and approved by Northwestern University Animal Care and Use Committee. Slices were prepared from newborn (P5-P10) CXCR4-EGPF mouse pups (www.gensat.org) as described previously (Marchionni et al., 2010), or, in a few cases, from GIN mice, which identify somatostatin-expressing interneurons (strain: FVB-Tg(GadGFP)45704Swn/J, Jackson Labs, see Oliva et al.,

GABAergic input to Cajal-Retzius cells

When recorded in whole-cell voltage-clamp configuration, identified neocortical Cajal-Retzius cells of the developing layer I (Fig. 1A, B and C) show rare and irregularly-occurring spontaneous synaptic events. These synaptic events were completely abolished by gabazine (12.5 μM, Fig. 1D), indicating that they were mediated by GABAA receptors. Compared to a control value of 66 ± 26 mHz, bath perfusion of gabazine decreased the spontaneous frequency to 0 ± 0 mHz, (n = 8, p < 0.05, paired t-test).

Discussion

To our knowledge, this work establishes for the first time two important novel results. First, we show that synaptically-released GABA is able to trigger action potentials in Cajal-Retzius cells via GABAA receptors. Second, we demonstrate that an important source of GABAergic input to Cajal-Retzius cells is massively controlled by the activation of mGlu1α receptors. Therefore, our data predict that conditions associated with sustained glutamate release, which may occur in vivo and lead to the

Conflict of interest

None.

Acknowledgments

This work was supported by the National Institute of Neurological Disorders and Stroke (grant number NS064135 to GM).

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