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Nogoa Restricts Synaptic Plasticity in the Adult Hippocampus on a Fast Time Scale

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Nogoa Restricts Synaptic Plasticity in the Adult Hippocampus on a Fast Time Scale NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale Andrea Delekatea, Marta Zagrebelskya, Stella Kramera,b, Martin E. Schwabb, and Martin Kortea,1 aDivision of Cellular Neurobiology, Zoological Institute, TU Braunschweig, 38106 Braunschweig, Germany; and bBrain Research Institute, University of Zurich and Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8057 Zurich, Switzerland Edited* by Hans Thoenen, Max Planck Institute of Neurobiology, Martinsried, Germany, and approved December 29, 2010 (received for review September 6, 2010) Whereas the role of NogoA in limiting axonal fiber growth and dominance plasticity continues after the end of the critical period, regeneration following an injury of the mammalian central nervous suggesting that NgR1 and PirB signaling stabilizes the neural cir- system (CNS) is well known, its physiological functions in the cuitry and limits experience-dependent plasticity. In addition, mature uninjured CNS are less well characterized. NogoA is mainly NgR1 signaling can influence LTP in concert with FGF2 (14) as expressed by oligodendrocytes, but also by subpopulations of well as long-term memory (15). neurons, in particular in plastic regions of the CNS, e.g., in the It is noteworthy that NogoA/NgR1 are expressed in pyramidal hippocampus where it is found at synaptic sites. We analyzed cells of the hippocampus (12), that their expression is regulated synaptic transmission as well as long-term synaptic plasticity (long- by neuronal activity (16, 17), and that NgR1 is located at syn- term potentiation, LTP) in the presence of function blocking anti- apses in the adult CNS (18). However, the physiological role of NogoA or anti-Nogo receptor (NgR) antibodies and in NogoA KO neuronal NogoA in the hippocampus of adult animals has remained largely unexplored (for a review see ref. 5). mice. Whereas baseline synaptic transmission, short-term plasticity Here we report a unique, acute physiological function of and long-term depression were not affected by either approach, fi NogoA in the mature hippocampus acting on a fast time scale. Our long-term potentiation was signi cantly increased following NogoA results suggest that NogoA is involved in specifically stabilizing or NgR1 neutralization. Synaptic potentiation thus seems to be re- synaptic weight. stricted by NogoA. Surprisingly, synaptic weakening was not af- fected by interfering with NogoA signaling. Mechanistically of in- Results terest is the observation that by blockade of the GABAA receptors Hippocampal Slices Treated with Function Blocking Antibodies Against normal synaptic strengthening reoccurred in the absence of NogoA NogoA. To study possible acute effects of NogoA in regulating signaling. The present results show a unique role of NogoA expressed synaptic plasticity, we treated wild-type (WT) mouse acute hip- in the adult hippocampus in restricting physiological synaptic plastic- pocampal slices with the NogoA-specific function blocking an- ity on a very fast time scale. NogoA could thus serve as an important tibody (Ab) 11c7 (19) or control Ab (anticyclosporin) for 1 h and negative regulator of functional and structural plasticity in mature induced under these conditions LTP at the CA3-CA1 Schaffer- neuronal networks. collateral pathway. Theta burst stimulation (TBS) to hippo- campal slices of adult mice (P40–P60) was applied 20 min after hanges in the connectivity of neurons—synaptic plasticity— baseline recording. The 11c7 Ab-treated slices showed already in Cregulate the fine-tuning of neuronal networks during de- the induction phase a higher LTP, which resulted in a significant velopment and during adult learning. Synaptic plasticity includes difference 55–60 min after TBS (Fig. 1A; P = 0.02, t test). The functional and structural modifications at neurons and may be the average potentiation in 11c7-treated WT slices was 168 ± 7.4% underlying mechanism for learning and memory processes (1). (n = 14 slices per 7 animals), whereas control Ab-treated slices The storage of new information therefore might depend on ever showed a potentiation of 141 ± 8.0% (n = 13 slices per 6 ani- changing neuronal networks. On the other hand, recent data in- mals) 55–60 min after the TBS. dicate that the large scale organization of neuronal networks is To investigate the role of NogoA in controlling protein-synthesis NEUROSCIENCE kept remarkably stable to maintain a constant flow of information dependent L-LTP, we recorded the post-TBS potentiation for 3 h and to support long-term memory storage (reviewed in ref. 2). in 11c7-treated WT slices compared with control Ab-treated ones In the CA1 region of the hippocampus, changes in neuronal (Fig. 1B). Indeed the difference between both treatments became activity can lead to changes in synaptic weight. Molecular mecha- even more pronounced and was highly significant 3 h after TBS nisms include here changes in the number or properties of neu- (P = 0.01, t test). The average potentiation in 11c7-treated WT rotransmitter receptors, retrograde messengers, structural changes slices was 158 ± 6.7% (n = 4/2) and 126 ± 5.7% (n = 4/2) in control at synapses, and activation of transcription/translation (3). What is Ab-treated slices, respectively. less clear is whether molecular mechanisms restricting changes in We next investigated the effect of 11c7 treatment on the ex- synaptic weight and thus stabilizing the synapse also play a role as pression of long-term depression (LTD), induced by a 15-min well. In this context it is interesting to note that preventing further low-frequency (1 Hz) stimulus (LFS) protocol. NogoA neutral- potentiation of a given set of synapses in a neuronal network can be ization did not induce any differences in LTD induction or induced by a homeostatic shutdown of long-term potentiation maintenance compared with control Ab-treated slices (Fig. 1C). (LTP) after intense stimulation (4). In the search for such molec- At 55–60 min after LFS, the average depression was 85 ± 2.2% ular stabilizers, we investigated the protein NogoA, which has been in 11c7 (n = 17/8) and 84 ± 1.9% in control (n = 18/10) Ab- identified as a negative regulator of structural changes in the CNS treated slices. (5). NogoA prevents neurite outgrowth in the adult CNS after injury (6) and regulates the progressive restriction of plasticity during development (7–9). In the adult CNS, the bulk of NogoA is Author contributions: M.Z. and M.K. designed research; A.D. and S.K. performed research; found in myelin, but interestingly, neuronal NogoA expression M.E.S. contributed new reagents/analytic tools; A.D., S.K., and M.K. analyzed data; and persists in those regions of the CNS that are known to be partic- M.Z., M.E.S., and M.K. wrote the paper. ularly plastic, e.g., the hippocampus and the olfactory system (10, The authors declare no conflict of interest. 11, see also ref. 12). In the mature CNS both known receptors for *This Direct Submission article had a prearranged editor. NogoA, Nogo66 receptor 1 (NgR1) and the paired Ig-like receptor 1To whom correspondence should be addressed. E-mail: [email protected]. B (PirB), negatively modulate activity-dependent synaptic plas- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ticity. In ngr1 knockout (9) and in pirB knockout mice (13), ocular 1073/pnas.1013322108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1013322108 PNAS | February 8, 2011 | vol. 108 | no. 6 | 2569–2574 Downloaded by guest on September 26, 2021 A increase in 11c7-treated slices, which is, however, not significantly different at any interstimulus interval (ISI) measured. Changes in the height of potentiation during the induction and maintenance of LTP could also be due to changes in baseline synaptic transmission. We therefore recorded an input-output curve, using the fiber volley as an indicator of presynaptic stim- ulation strength and plotted a given fiber volley size against the fEPSP slope (Fig. 1E). With this approach we could not find any significant differences between 11c7 or control Ab-treated slices. To confirm the penetration of the NogoA blocking Ab and identify its binding sites, the recorded hippocampal slices un- derwent immunostaining for mouse antibodies. We observed high levels of 11c7 Ab bound to possibly Mossy cells of the polymorphic layer of the dentate gyrus (Fig. S1 A and F, open arrows) and also especially to pyramidal cells of the CA3 region (Fig. S1 A, C, and D, closed arrows) up to 200 μm into the slice. In the latter, both the cell bodies and the dendrites were labeled (Fig. S1C). In the CA1 B D region, strongly labeled cells were sparser and only the cell bodies were stained (Fig. S1 A and E, arrowheads). No staining could be observed in slices treated with control antibodies (Fig. S1 B and G–I) indicating a specific binding of the 11c7 Ab. This is in line with EM data and biochemical evidence (14, 21, 22). Taken together, these results clearly show that NogoA is specifically involved in restricting the height of synaptic poten- tiation on a fast time scale. On the other hand, NogoA signaling is not mediating or preventing mechanisms of synaptic weaken- ing and it does not significantly change properties of baseline C E synaptic transmission. Role of the Nogo Receptor NgR1 on Processes of Synaptic Plasticity. To analyze whether the role of NogoA on hippocampal LTP involves the known Nogo receptor (NgR) pathway, we tested whether the blockade of the NgR would have an effect on the induction and maintenance of LTP. We applied a function blocking anti-NgR Ab (23) to WT acute slices with the same procedures we used for the anti-NogoA Ab. Fig. 2A shows that the blockade of NgR also leads to higher levels of potentiation fol- lowing TBS compared with control Ab treatment.
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