Emergence of brain-derived neurotrophic factor-induced postsynaptic potentiation of NMDA currents during the postnatal maturation of the Kolliker-Fuse nucleus of rat.
Journal: 2008/June - Journal of Physiology
ISSN: 1469-7793
Abstract:
The Kölliker-Fuse nucleus (KF) contributes essentially to respiratory pattern formation and adaptation of breathing to afferent information. Systems physiology suggests that these KF functions depend on NMDA receptors (NMDA-R). Recent investigations revealed postnatal changes in the modulation of glutamatergic neurotransmission by brain-derived neurotrophic factor (BDNF) in the KF. Therefore, we investigated postnatal changes in NMDA-R subunit composition and postsynaptic modulation of NMDA-R-mediated currents by BDNF in KF slice preparations derived from three age groups (neonatal: postnatal day (P) 1-5; intermediate: P6-13; juvenile: P14-21). Immunohistochemistry showed a developmental up-regulation of the NR2D subunit. This correlated with a developmental increase in decay time of NMDA currents and a decline of desensitization in response to repetitive exogenous NMDA applications. Thus, developmental up-regulation of the NR2D subunit, which reduces the Mg(2+) block of NMDA-R, causes these specific changes in NMDA current characteristics. This may determine the NMDA-R-dependent function of the mature KF in the control of respiratory phase transition. Subsequent experiments revealed that bath-application of BDNF progressively potentiated these repetitively evoked NMDA currents only in intermediate and juvenile age groups. Pharmacological inhibition of protein kinase C (PKC), as a downstream component of the BDNF-tyrosine kinase B receptor (trkB) signalling, prevented BDNF-induced potentiation of NMDA currents. BDNF-induced potentiation of NMDA currents in later developmental stages might be essential for synaptic plasticity during the adaptation of the breathing pattern in response to peripheral/central commands. The lack of plasticity in neonatal neurones strengthens the hypothesis that the respiratory network becomes permissive for activity-dependent plasticity with ongoing postnatal development.
Relations:
Content
Citations
(12)
References
(58)
Drugs
(1)
Chemicals
(2)
Genes
(2)
Organisms
(4)
Processes
(4)
Anatomy
(1)
Similar articles
Articles by the same authors
Discussion board
J Physiol 586(Pt 9): 2331-2343

Emergence of brain-derived neurotrophic factor-induced postsynaptic potentiation of NMDA currents during the postnatal maturation of the Kölliker–Fuse nucleus of rat

Click here to view.(4.2M, tif)
Department of Neuro and Sensory Physiology, University Medicine Göttingen, Georg August University, Humboldtallee 23, 37073 Göttingen, Germany
Deutsche Forschungsgemeinschaft Research Center for Molecular Physiology of the Brain (CMPB), 37073 Göttingen, Germany
Bernstein Center for Computational Neurosciences (BCCN), 37073 Göttingen, Germany
Corresponding author M. Dutschmann: Department of Neuro and Sensory Physiology, University Medicine Göttingen, Georg August University, Humboldtallee 23, 37073 Göttingen, Germany. Email: ed.gdwg@hcstudm
This paper has online supplemental material.
This paper has online supplemental material.
Received 2007 Nov 27; Accepted 2008 Mar 3.

Abstract

The Kölliker–Fuse nucleus (KF) contributes essentially to respiratory pattern formation and adaptation of breathing to afferent information. Systems physiology suggests that these KF functions depend on NMDA receptors (NMDA-R). Recent investigations revealed postnatal changes in the modulation of glutamatergic neurotransmission by brain-derived neurotrophic factor (BDNF) in the KF. Therefore, we investigated postnatal changes in NMDA-R subunit composition and postsynaptic modulation of NMDA-R-mediated currents by BDNF in KF slice preparations derived from three age groups (neonatal: postnatal day (P) 1–5; intermediate: P6–13; juvenile: P14–21). Immunohistochemistry showed a developmental up-regulation of the NR2D subunit. This correlated with a developmental increase in decay time of NMDA currents and a decline of desensitization in response to repetitive exogenous NMDA applications. Thus, developmental up-regulation of the NR2D subunit, which reduces the Mg block of NMDA-R, causes these specific changes in NMDA current characteristics. This may determine the NMDA-R-dependent function of the mature KF in the control of respiratory phase transition. Subsequent experiments revealed that bath-application of BDNF progressively potentiated these repetitively evoked NMDA currents only in intermediate and juvenile age groups. Pharmacological inhibition of protein kinase C (PKC), as a downstream component of the BDNF–tyrosine kinase B receptor (trkB) signalling, prevented BDNF-induced potentiation of NMDA currents. BDNF-induced potentiation of NMDA currents in later developmental stages might be essential for synaptic plasticity during the adaptation of the breathing pattern in response to peripheral/central commands. The lack of plasticity in neonatal neurones strengthens the hypothesis that the respiratory network becomes permissive for activity-dependent plasticity with ongoing postnatal development.

Abstract

The Kölliker–Fuse nucleus (KF) within the dorsolateral pons is an essential part of the respiratory network (St-John, 1998; Alheid et al. 2004; Ezure, 2004; Dutschmann & Herbert, 2006). In the absence of afferent feedback from pulmonary stretch receptors, the KF is crucially involved in N-methyl-d-aspartate receptor (NMDA-R)-dependent mediation of inspiratory/expiratory phase transition of the respiratory cycle (Bianchi et al. 1995; Bonham, 1995; St-John, 1998). Importantly, the KF receives second order synaptic inputs from somato- (e.g. spinal trigeminal tract; Feil & Herbert, 1995) and viscero-sensory relays (e.g. the nucleus of solitary tract (NTS); Herbert et al. 1990). Thus, it is involved in the adaptation of the breathing pattern in response to various kinds of afferent information. During the processing of afferent information, NMDA-R again may play a dominant role (Dutschmann & Herbert, 1998; Dutschmann et al. 1998; Siniaia et al. 2000; Okazaki et al. 2002; Takano & Kato, 2003; Dutschmann et al. 2004; Song & Poon, 2004). Since glutamatergic neurotransmission via NMDA-R is linked to synaptic plasticity (Sheng & Kim, 2002), it is not surprising that KF-mediated plasticity apparently depends on neurotransmission via NMDA-R (Dutschmann et al. 2004; Song & Poon, 2004). NMDA-R-mediated plasticity is linked to NMDA-R subunit composition (Monyer et al. 1994; Cull-Candy et al. 2001) and also involves intracellular signalling pathways, which are activated either directly by Ca influx or secondarily by the release of neuromodulators. One of these neuromodulators is brain-derived neurotrophic factor (BDNF), acting on tyrosine kinase B receptor (trkB) which can induce a rapid phosphorylation of different NMDA-R subunits (Suen et al. 1997; Lin et al. 1998; Slack et al. 2004). This, in turn, modulates NMDA-R conductance (Levine et al. 1998; Yamada et al. 2002; Kim et al. 2006; Xu et al. 2006) and is linked to learning and memory processes (Lu, 2003). A recent publication showed that BDNF becomes a potent modulator of glutamatergic neurotransmission during the postnatal ontogeny of the KF (Kron et al. 2007a). Thereby, BDNF is potentially released in the KF via pathways arising from the NTS, which densely expresses BDNF (Wang et al. 2006).

Importantly, the KF is immature at birth. Previous studies demonstrated that the postnatal maturation of the KF is reflected in changes of morphological and synaptic properties (Dutschmann et al. 2004; Kron et al. 2007a,b) These developmental changes are most likely also associated with the NMDA-R-dependent processing of afferent inputs which are silent or not functional prenatally. Interestingly, the adult KF contains high mRNA levels for the NMDA-R subunit 2D (NR2D, Guthmann & Herbert, 1999), whereas in other brain regions the NR2D subunit is down-regulated during postnatal development (Akazawa et al. 1994; Monyer et al. 1994; Cull-Candy et al. 2001). This implicates a different developmental course of NR2D expression in the KF. However, the developmental changes of NR2D subunit expression until now have not been investigated.

The present study investigated developmental changes in: (i) NMDA-R subunit NR2D expression, (ii) NMDA current characteristics and (iii) postsynaptic modulation of NMDA currents by BDNF in the developing KF. We show that developmental up-regulation of the NMDA-R subunit NR2D corresponds with an increasing decay time of NMDA currents and a lack of desensitization. Furthermore, BDNF caused a progressive potentiation of NMDA currents in the juvenile KF. The BDNF-evoked potentiation could be blocked by inhibition of protein kinase C (PKC), a downstream component in trkB-mediated signalling pathways, and by the chelation of intracellular Ca with BAPTA.

Numbers represent means ±s.e.m. of NR2B- and NR2D-positive cells within 10 000 μm of each region. KF, Kölliker–Fuse nucleus; pFRG, parafacial respiratory group; pre-BötC, pre-Bötzinger complex; VRG, ventral respiratory group.

Acknowledgments

This study was supported by grants of the DFG – Research Center Molecular Physiology of the Brain (CMPB; W.Z.) and Bernstein Center for Computational Neurosciences (BCCN, 01GQ0432, M.D.). We thank A. Bischoff for excellent technical assistance and Dr U. Dürr for valuable suggestions on the manuscript.

Acknowledgments
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.