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  • The observed increase in Bdnf mRNA occurred h after treatmen

    2019-11-13

    The observed increase in Bdnf1 mRNA occurred 1 h after treatment indicates participation of BDNF in early plasticity and subsequently mnemonic processes. Most of the evidence regarding the importance of BDNF for memory formation derived from electrophysiological studies that utilized the molecular correlate of memory, referred to as long-term potentiation (LTP) (Chen et al., 2010, Cunha et al., 2010, Dixon, 1959). LTP consists of a labile early phase (E-LTP), lasting 1 to 3 h, followed by a more stable late phase (L-LTP) characterized by protein synthesis (Reymann & Frey, 2007). Although there is a plethora of studies establishing the importance of BDNF signaling for the L-LTP and subsequently long-term memory (Cunha et al., 2010, Edelmann et al., 2014, Reymann and Frey, 2007), it has been shown that BDNF is also important for the early phase of LTP. Considering the time point that we measure gene expression, our results underscore the involvement of BDNF in the early phase of memory formation. There is a growing body of evidence indicating the importance of pre- or post-synaptic BNDF signaling for E-LTP and early memory processes (for a review see Edelmann et al., 2014). The differential findings regarding the site of BDNF action could be the result of different stimulation protocols or stimulation of different areas in the hippocampus. A study from Mohajerani et al. reported a distinct role of BDNF signaling in the different phases of LTP (Mohajerani, Sivakumaran, Zacchi, Aguilera, & Cherubini, 2007). Specifically, it was shown that during E-LTP, BDNF acts at the presynaptic cell to enhance neurotransmitter release, while at the L-LTP its action is mainly located at the postsynaptic site, where it promotes protein synthesis. Another study showed that the transcription of Bdnf gene occurs within thirty minutes upon stimulation of cortical cell culture n methyl d aspartic acid (Tao, Finkbeiner, Arnold, Shaywitz, & Greenberg, 1998). The above observation regarding immediate transcription of Bdnf in vitro was subsequently confirmed in a memory paradigm in rats. In more detail, it was shown that Bdnf is immediately transcribed in the CA1 region of the hippocampus during contextual learning in the fear conditioning test (Hall, Thomas, & Everitt, 2000). Although the role of BDNF in mnemonic processes is well established, there is scarcity of evidence associating BDNF with pattern separation. Nevertheless, a recent study has shown that BDNF in the DG has an eminent role in the early memory processes of pattern separation (Bekinschtein et al., 2013). Specifically, intra-DG blockage of BDNF, either before or after the acquisition phase of the pattern separation task, impaired rats’ ability to separate similar representations. Importantly, biochemical analysis showed an increase in BDNF protein levels in the DG when animals were sacrificed within 1 h after learning the pattern separation task. Finally, intrahippocampal injection of human recombinant BDNF, after the acquisition phase of the pattern separation task, enhanced discrimination of similar environmental cues. These findings provide ground evidence for the involvement of BDNF in pattern separation memory (Bekinschtein et al., 2013). Also the role of BDNF n methyl d aspartic acid during pattern separation processes was shown to be mediated by interaction of BDNF with adult-born immature cells in the DG (Bekinschtein et al., 2014). Our study corroborates the above findings regarding the role of BDNF in pattern separation and provides further evidence for the involvement of Bdnf1 during the early memory processes of this mnemonic task. Despite the significant increase in Bdnf1 mRNA levels after DNMT inhibition, the expression of Bdnf4 and Bdnf9 was unaltered. It is particularly surprising that Bdnf4 is not affected by the DNMT inhibitor, as the promoter of the Bdnf4 exon is known to be susceptible to epigenetic changes (Kotera et al., 2004) and has an eminent role in the processes of learning and memory in rodents (Lubin, 2011). A possible explanation for the above observation could be related to the differential involvement of BDNF transcripts in distinct memory processes of different cognitive tasks. For example, in a study in which the contextual fear conditioning paradigm was used, it was shown that exposure to a novel context leads to upregulation of Bdnf1 in the hippocampus within 2 h, while consolidation of associative memory was accompanied by elevation in expression of Bdnf4 (Lubin, Roth, & Sweatt, 2008). Interestingly, a different study in which they used the object recognition memory task showed that short-term recognition memory is positively correlated with increased methylation of Bdnf1 in the hippocampus of the rats, though BDNF protein levels in the hippocampus were decreased. Of note, an opposite effect was observed for BDNF in the perirhinal cortex (Muñoz, Aspé, Contreras, & Palacios, 2010). Therefore, the memory process and task specific requirement of different BDNF transcripts in brain structures could explain the differential results regarding expression of the BDNF splice variants after treatment. Although in our study we did not measure protein levels after drug administration, it would be interesting to check if our increases in Bdnf1 mRNA levels could subsequently result in decreased or increased BDNF synthesis in different brain areas.