Novel Mechanisms of Memory by Karl Peter Giese & Kasia Radwanska

Author:Karl Peter Giese & Kasia Radwanska
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

5.4 Is MIS Generation Required for Contextual Fear LTM Formation in T286A Mutants?

To establish that MIS generation is required for contextual fear LTM in T286A mutants it is necessary to specifically block this type of synaptogenesis. So far only little is known about the molecular mechanisms underlying MIS generation. The induction of MIS generation requires NMDA receptor activation (Nikonenko et al. 2003). PSD-95 overexpression is sufficient to induce MIS generation (Nikonenko et al. 2008). This overexpression leads to activation of neuronal nitric oxide synthase that produces a retrograde messenger to attract a presynaptic terminal onto the dendritic spine (Nikonenko et al. 2008). PSD-95 protein is locally translated in dendritic spines from pre-existing stores of mRNA after synaptic activation (Kelleher et al. 2004; Lee et al. 2005; Swiech et al. 2008; Belelovsky et al. 2009). Accordingly PSD-95 protein expression is not sensitive to block of transcription (Lee et al. 2005; Belelovsky et al. 2009) but is regulated by the activity of mammalian target of rapamycin (mTOR) signaling followed by protein synthesis (Lee et al. 2005; Belelovsky et al. 2009).

We analysed the regulation of PSD-95 expression in hippocampal area CA1 after contextual fear conditioning in the T286A mutants (Radwanska et al. 2011). Only the training conditions that lead to LTM formation cause an upregulation of PSD-95. Further, we found that the same amount of massed training does not upregulate PSD-95 expression in wild-type mice, as expected as these mice do not generate MIS. Thus, we found a perfect correlation between MIS generation and PSD-95 overexpression. Further, we showed that the PSD-95 upregulation is blocked by rapamycin, a specific blocker of mTOR signalling (Radwanska et al. 2011). Finally, post-training administration of rapamycin also blocks contextual LTM in T286A mutants (Radwanska et al. 2011) (Fig. 5.2). Taken together, these studies strongly suggest that MIS generation is required for contextual LTM in T286A mutants. As shown in Fig. 5.3, we propose a new model of LTM formation when LTP is impaired.

Fig. 5.2Contextual LTM formation requires mTOR signaling and protein synthesis in the dorsal hippocampus in the T286A mutants. WT mice and T286A mutants were trained with massed foreground conditioning. (a) Anisomycin (225 mg/kg) was intraperitoneally (IP) injected immediately after training. Contextual LTM was tested 24 h later. (b) Rapamycin (2.5 μg/side) or (c) actinomycin D (10 ng/side) were bilaterally injected into dorsal hippocampus (IdH) immediately after training and 24 h after conditioning the animals were tested for contextual LTM. (d) Training-induced PSD95 overexpression requires mTOR signaling in the dorsal hippocampus in the T286A mutants. Rapamycin (2.5 μg/side) was bilaterally injected into dorsal hippocampus (IdH) immediately after conditioning. The ventral and dorsal hippocampi were collected 2 h after training and lysates were assayed by immunoblotting. Reprinted from Radwanska et al. (2011)

Download

Copyright Disclaimer:
This site does not store any files on its server. We only index and link to content provided by other sites. Please contact the content providers to delete copyright contents if any and email us, we'll remove relevant links or contents immediately.