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Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain


The induction of associative synaptic plasticity in the mammalian central nervous system classically depends on coincident presynaptic and postsynaptic activity1,2. According to this principle, associative homosynaptic long-term potentiation (LTP) of excitatory synaptic transmission can be induced only if synaptic release occurs during postsynaptic depolarization1,2. In contrast, heterosynaptic plasticity in mammals is considered to rely on activity-independent, non-associative processes3,4,5,6,7,8. Here we describe a novel mechanism underlying the induction of associative LTP in the lateral amygdala (LA). Simultaneous activation of converging cortical and thalamic afferents specifically induced associative, N-methyl-d-aspartate (NMDA)-receptor-dependent LTP at cortical, but not at thalamic, inputs. Surprisingly, the induction of associative LTP at cortical inputs was completely independent of postsynaptic activity, including depolarization, postsynaptic NMDA receptor activation or an increase in postsynaptic Ca2+ concentration, and did not require network activity. LTP expression was mediated by a persistent increase in the presynaptic probability of release at cortical afferents. Our study shows the presynaptic induction and expression of heterosynaptic and associative synaptic plasticity on simultaneous activity of converging afferents. Our data indicate that input specificity of associative LTP can be determined exclusively by presynaptic properties.

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Figure 1: Induction of LTPHA at cortical, but not at thalamic, afferent synapses by simultaneous Poisson-train stimulation of thalamic and cortical afferents.
Figure 2: Induction of LTPHA does not depend on postsynaptic activity, but is dependent on NMDA receptor activation and Ca2+.
Figure 3: Network activity is not required for the induction of LTPHA.
Figure 4: Heterosynaptic, NMDA-receptor-dependent increase of release probability at cortical afferents after stimulation of thalamic afferents.


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We thank B. Gähwiler, C. Heuss, A. Matus, B. Poulain and E. Seifritz for discussions and comments on the manuscript. This work was supported by the Borderline Personality Disorder Research Foundation, the Swiss National Science Foundation and the Novartis Research Foundation.

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Correspondence to Andreas Lüthi.

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Humeau, Y., Shaban, H., Bissière, S. et al. Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain. Nature 426, 841–845 (2003).

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