Elsevier

Neuroscience Research

Volume 61, Issue 2, June 2008, Pages 192-200
Neuroscience Research

Brain-derived neurotrophic factor-mediated retrograde signaling required for the induction of long-term potentiation at inhibitory synapses of visual cortical pyramidal neurons

https://doi.org/10.1016/j.neures.2008.02.006Get rights and content

Abstract

High-frequency stimulation (HFS) induces long-term potentiation (LTP) at inhibitory synapses of layer 5 pyramidal neurons in developing rat visual cortex. This LTP requires postsynaptic Ca2+ rise for induction, while the maintenance mechanism is present at the presynaptic site, suggesting presynaptic LTP expression and the necessity of retrograde signaling. We investigated whether the supposed signal is mediated by brain-derived neurotrophic factor (BDNF), which is expressed in pyramidal neurons but not inhibitory interneurons. LTP did not occur when HFS was applied in the presence of the Trk receptor tyrosine kinase inhibitor K252a in the perfusion medium. HFS produced LTP when bath application of K252a was started after HFS or when K252a was loaded into postsynaptic cells. LTP did not occur in the presence of TrkB-IgG scavenging BDNF or function-blocking anti-BDNF antibody in the medium. In cells loaded with the Ca2+ chelator BAPTA, the addition of BDNF to the medium enabled HFS to induce LTP without affecting baseline synaptic transmission. These results suggest that BDNF released from postsynaptic cells activates presynaptic TrkB, leading to LTP. Because BDNF, expressed activity dependently, regulates the maturation of cortical inhibition, inhibitory LTP may contribute to this developmental process, and hence experience-dependent functional maturation of visual cortex.

Introduction

Long-term potentiation (LTP) of inhibitory synaptic transmission is easily produced by high-frequency stimulation (HFS) in layer 5 pyramidal neurons of developing rat visual cortex (Komatsu, 1994). This inhibitory LTP requires a transient elevation of intracellular Ca2+ in postsynaptic cells in response to HFS for induction (Komatsu, 1996), like most LTP at excitatory synapses (Tsumoto, 1992, Malenka and Bear, 2004). This Ca2+ elevation likely results from phospholipase C (PLC) activation, inositol trisphosphate (IP3) formation and Ca2+ release from internal stores via IP3 receptor activation (Komatsu, 1996).

The maintenance of this LTP requires neural activity, spike firing of presynaptic inhibitory cells at some frequency, which is lower than the frequency of test stimulation (0.1 Hz) usually used in LTP studies (Komatsu and Yoshimura, 2000). Such activity dependence of maintenance has not been documented for long-term synaptic modifications other than this inhibitory LTP and N-methyl-d-aspartate (NMDA) receptor-independent LTP at visual cortical excitatory synapses (Liu et al., 2004). According to our previous study on inhibitory LTP in layer 5 cells (Komatsu and Yoshimura, 2000), the maintenance is mediated by presynaptic Ca2+ entry associated with action potentials through multiple types of high-threshold Ca2+ channels, which activates Ca2+-dependent reactions different from those triggering transmitter release.

Although the expression site of this LTP remains to be determined, it is thus likely that LTP requires anterograde or retrograde signaling between pre- and postsynaptic cells irrespective of the expression site. If LTP is expressed presynaptically, some information must be sent backwards from the postsynaptic to the presynaptic cells during induction. In sensory cortex, brain-derived neurotrophic factor (BDNF) is expressed in pyramidal neurons but not inhibitory interneurons, while TrkB, the high-affinity receptor for BDNF, is expressed in both cells (Cellerino et al., 1996, Rocamora et al., 1996, Gorba and Wahle, 1999). BDNF can be released from the somatodendritic domain of pyramidal neurons in an activity-dependent manner via intracellular Ca2+ elevation (Canossa et al., 1997, Hartmann et al., 2001, Kojima et al., 2001, Balkowiec and Katz, 2002, Gärtner and Staiger, 2002). Therefore, in the present study we tested whether BDNF mediates a retrograde signal for the production of LTP at inhibitory synapses of layer 5 pyramidal neurons and obtained results supporting that hypothesis.

Section snippets

Animals and slice preparations

We deeply anesthetized pigmented (Long–Evans) rats at postnatal 20–29 days with isoflurane before the whole brain was removed from the skull and immersed in an ice-cold oxygenated (95% O2 and 5% CO2) artificial cerebrospinal fluid (ACSF) containing (in mM) 124 NaCl, 5 KCl, 1.3 MgSO4, 4 CaCl2, 1.2 KH2PO4, 26 NaHCO3, and 10 glucose. Then, coronal slices of primary visual cortex (400 μm thick) were prepared using a Microslicer (DTK-1000, Dosaka, Kyoto, Japan) and kept in a recovery chamber perfused

Results

Whole-cell voltage-clamp recording from layer 5 pyramidal neurons was conducted in visual cortical slices of developing rats at postnatal 20–29 days, when LTP of GABAA receptor-mediated inhibitory synaptic transmission occurs most frequently (Komatsu, 1994). IPSCs evoked by layer 4 stimulation were recorded from these neurons held at 0 mV under pharmacological blockade of excitatory synaptic transmission. One of the two pairs of stimulating electrodes placed in layer 4 was used to test the

Discussion

The present study demonstrated that the induction of LTP at inhibitory synapses of layer 5 pyramidal neurons requires the activation of TrkB receptors by BDNF. Our present and previous studies (Komatsu, 1996, Komatsu and Yoshimura, 2000) suggest that BDNF, released from postsynaptic cells via HFS-induced IP3 receptor-mediated Ca2+ elevation, activates TrkB receptors at the presynaptic nerve terminals, leading to LTP.

Acknowledgements

This study was supported by grants from the Japanese Ministry of Education, Culture, Science, Sports and Technology to Y.Y. (17500208 and 18021018) and Y.K. (17300101, 18021017) and from the Sumitomo Foundation to Y.Y.

References (52)

  • I. Abidin et al.

    Reduced presynaptic efficiency of excitatory synaptic transmission impairs LTP in the visual cortex of BDNF-heterozygous mice

    Eur. J. Neurosci.

    (2006)
  • Y. Akaneya et al.

    Brain-derived neurotrophic factor blocks long-term depression in rat visual cortex

    J. Neurophysiol.

    (1996)
  • Y. Akaneya et al.

    Brain-derived neurotrophic factor enhances long-term potentiation in rat visual cortex

    J. Neurosci.

    (1997)
  • A. Balkowiec et al.

    Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons

    J. Neurosci.

    (2002)
  • A. Bartoletti et al.

    Heterozygous knock-out mice for brain-derived neurotrophic factor show a pathway-specific impairment of long-term potentiation but normal critical period for monocular deprivation

    J. Neurosci.

    (2002)
  • R.J. Cabelli et al.

    Changing patterns of expression and subcellular localization of trkB in the developing visual system

    J. Neurosci.

    (1996)
  • M. Canossa et al.

    Neurotrophin release by neurotrophins: Implications for activity-dependent neuronal plasticity

    Proc. Natl. Acad. Sci. U.S.A.

    (1997)
  • M. Canossa et al.

    Regulated secretion of neurotrophins by metabotropic glutamate group I (mGluRI) and Trk receptor activation is mediated via phospholipase C signalling pathways

    EMBO J.

    (2001)
  • E. Castrén et al.

    Light regulates expression of brain-derived neurotrophic factor mRNA in rat visual cortex

    Proc. Natl. Acad. Sci. U.S.A.

    (1992)
  • A. Cellerino et al.

    The distribution of brain-derived neurotrophic factor and its receptor trkB in parvalbumin-containing neurons of the rat visual cortex

    Eur. J. Neurosci.

    (1996)
  • R.H. Fryer et al.

    Developmental and mature expression of full-length and truncated trkB receptors in the rat forebrain

    J. Comp. Neurol.

    (1996)
  • A. Gärtner et al.

    Neurotrophin secretion from hippocampal neurons evoked by long-term potentiation-inducing electrical stimulation patterns

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • T. Gorba et al.

    Expression of trkB and trkC but BDNF mRNA in neurochemically identified interneurons in rat visual cortex in vivo and in organotypic cultures

    Eur. J. Neurosci.

    (1999)
  • P. Gubellini et al.

    Endogenous neurotrophins are required for the induction of GABAergic long-term potentiation in the neonatal rat hippocampus

    J. Neurosci.

    (2005)
  • M. Hartmann et al.

    Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses

    EMBO J.

    (2001)
  • T.K. Hensch

    Critical period plasticity in local cortical circuits

    Nat. Rev. Neurosci.

    (2005)
  • Cited by (53)

    • Pinpointing the locus of GABAergic vulnerability in Alzheimer's disease

      2023, Seminars in Cell and Developmental Biology
    • Sleep and Brain Development

      2019, Handbook of Behavioral Neuroscience
    • Metabolic profile study of 7, 8-dihydroxyflavone in monkey plasma using high performance liquid chromatography–tandem mass spectrometry

      2017, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
      Citation Excerpt :

      Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family [1]. As the most widely distributed neurotrophin in central nervous system, it plays a crucial role in synapse plasticity [2], neuronal growth and survival [3–5], and memory retention [6,7] by binding to its specific cognate receptor tropomyosin-receptor-kinase B (TrkB). However, clinical trials using recombinant BDNF are disappointingly negative, presumably because of the difficult delivery to the central nervous system and the poor pharmacokinetic profile [8,9].

    View all citing articles on Scopus
    View full text