Brain-derived neurotrophic factor-mediated retrograde signaling required for the induction of long-term potentiation at inhibitory synapses of visual cortical pyramidal neurons
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.
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2017, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life SciencesCitation 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].