Hierarchical order of coexisting pre- and postsynaptic forms of long-term potentiation at synapses in amygdala

Abstract

Synaptic rules that may determine the interaction between coexisting forms of long-term potentiation (LTP) at glutamatergic central synapses remain unknown. Here, we show that two mechanistically distinct forms of LTP could be induced in thalamic input to the lateral nucleus of the amygdala (LA) with an identical presynaptic stimulation protocol, depending on the level of postsynaptic membrane polarization. One form of LTP, resulting from pairing of postsynaptic depolarization and low-frequency presynaptic stimulation, was both induced and expressed postsynaptically ("post-LTP"). The same stimulation in the absence of postsynaptic depolarization led to LTP, which was induced and expressed presynaptically ("pre-LTP"). The inducibility of coexisting pre-and postsynaptic forms of LTP at synapses in thalamic input followed a well-defined hierarchical order, such that pre-LTP was suppressed when post-LTP was induced. This interaction was mediated by activation of cannabinoid type 1 receptors by endogenous cannabinoids released in the lateral nucleus of the amygdala in response to activation of the type 1 metabotropic glutamate receptor. These results suggest a previously unknown mechanism by which the hierarchy of coexisting forms of long-term synaptic plasticity in the neural circuits of learned fear could be established, possibly reflecting the hierarchy of memories for the previously experienced fearful events according to their aversiveness level.synaptic transmission | glutamate | plasticity | endocannabinoids F ear conditioning is one of the best experimental models of associative learning, which results from memorizing the temporal association between biologically neutral conditioned stimuli (CS) and aversive unconditioned stimuli (US) during behavioral training (1, 2). In the course of auditory fear conditioning, signals produced by the acoustic conditioned stimulus enter the lateral nucleus of the amygdala (LA) through projections originating in the auditory thalamus (thalamic input) and indirect projections from the auditory cortex (cortical input) (3). The acquisition of fear memory to auditory stimulation is mediated by long-term potentiation (LTP)-like synaptic enhancements in the CS pathways, including both cortical and thalamic inputs to the LA (4-9). Different forms of LTP could be observed, however, at synapses in the amygdala (7,8,(10)(11)(12) as well as in other regions of the brain (13, 14), depending on the presynaptic activity levels and degree of postsynaptic depolarization. Thus, conventional pairing-induced LTP and spike timing-dependent LTP in thalamic projections to the LA are expressed postsynaptically and may implicate trafficking of AMPA receptors at stimulated synapses ("post-LTP") (8, 15), whereas LTP in cortical input to the LA is expressed presynaptically, resulting from an increase in the probability of neurotransmitter release ("pre-LTP") (7). Little is known, however, about whether the coexisting forms of LTP at glutamatergic synapses interact with each other during the induction ...

Asymmetrical Synaptic Cooperation between Cortical and Thalamic Inputs to the Amygdale

“…To test this, we measured the PPF ratio before and after LTP induction. Although changes in PPF ratio can exceptionally be induced by postsynaptic mechanisms (Wang and Kelly, 1997), it is generally the case that changes in PPF reflect a modulation of the presynaptic release probability (Shin et al, 2010;Tsvetkov et al, 2002). We found that LTP induction did not change PPF ratio (%baseline) in cortical inputs but significantly reduced the PPF ratio in thalamic inputs, a reduction that was still evident 1 h after LTP induction ( Figure 2e).…”

“…These results suggest that induction of LTP in the thalamic input had a presynaptic expression mechanism that was not observed in cortical L-LTP induction. As glutamate (GluR)5 kainate Synaptic cooperation in the amygdala R Fonseca et al (KA) receptor activation has been implicated in the induction of presynaptic forms of thalamic LTP associated with a decrease in the PPF (Shin et al, 2010), to corroborate our results we tested the effect of inhibiting KA receptors in the thalamic LTP induction. We found that application of UBP302 (1 mM), an inhibitor of KA receptors, during the stimulation of the thalamic input blocked LTP induction (Supplementary Figure S1A (b) Application of Verapamil (50 mMD) blocks thalamic L-LTP, whereas application of AP-5 (50 mMB) results in nonsignificant decrease in LTP (T1 thalamic 212 ± 18%, n ¼ 9; thalamic (AP-5) 161 ± 13.7%, n ¼ 9; thalamic (Verapamil) 150 ± 22%, n ¼ 9; T2 thalamic 183 ± 14.8%, n ¼ 9; thalamic (AP-5) 147 ± 18.5%, n ¼ 9; thalamic (Verapamil) 114 ± 11.7%, n ¼ 9).…”

“…Although it is generally accepted that the thalamic LA and cortical LA LTP can be induced and expressed postsynaptically, recent reports have shown that LTP induced at the cortical and thalamic inputs can also be expressed presynaptically (Huang and Kandel, 1998;Shin et al, 2010). In addition, the activation of L-type VGCC has been implicated in the induction of a presynaptic form of LTP (Fourcaudot et al, 2009).…”

“…In the case of coincident activation of thalamic and cortical inputs, a heterosynaptic NMDA-dependent form of LTP is induced and expressed through presynaptic mechanisms (Humeau et al, 2003). Interestingly, postsynaptic induction of thalamic LTP can suppress thalamic presynaptic LTP via the CB1 endocannabinoid (eCB) receptors (Shin et al, 2010). How these different forms of thalamic and cortical LTP are orchestrated and the cellular mechanisms involved in the maintenance of thalamic and cortical association are not clear.…”

“…In addition, the persistence of LTP involves de novo protein synthesis and postsynaptic AMPA receptor insertion (Rumpel et al, 2005). However, different forms of LTP have been described in thalamic LA and cortical LA synapses, with both inputs displaying postsynaptic and presynaptic forms of LTP depending on the exact afferent stimulation protocol and the degree of postsynaptic depolarization (Fourcaudot et al, 2009;Huang and Kandel, 1998;Shin et al, 2010). In the case of coincident activation of thalamic and cortical inputs, a heterosynaptic NMDA-dependent form of LTP is induced and expressed through presynaptic mechanisms (Humeau et al, 2003).…”