Dendritic Spine Heterogeneity Determines Afferent-Specific Hebbian Plasticity in the Amygdala

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 ...

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confidence: 99%

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

Shin¹,

Tully

et al. 2010

“…Sensory information reaches the LA by two main glutamatergic pathways originating in sensory thalamus and cortex (1). The induction and expression of LTP at thalamo-LA synapses is mediated by Ca 2ϩ influx through postsynaptic NMDA receptors eventually leading to the recruitment of new AMPA receptors to the postsynaptic membrane (4)(5)(6)(7). LTP at cortico-LA synapses is mediated by contrasting mechanisms.…”

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confidence: 99%

“…LTP at cortico-LA synapses is mediated by contrasting mechanisms. Pairing of presynaptic stimulation with postsynaptic depolarization triggers LTP that is induced postsynaptically (5,(8)(9)(10) and may involve both pre-and postsynaptic expression mechanisms, such as an increase in glutamate release and the recruitment of postsynaptic AMPA receptors (7)(8)(9)(10). In contrast, coactivation of the thalamo-and the cortico-LA pathways results in NMDA receptor-dependent LTP that is induced and expressed entirely via presynaptic mechanisms (10,11).…”

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confidence: 99%

cAMP/PKA signaling and RIM1α mediate presynaptic LTP in the lateral amygdala

Fourcaudot

Gambino

Humeau

et al. 2008

Self Cite

109

NMDA receptor-dependent long-term potentiation (LTP) of glutamatergic synaptic transmission in sensory pathways from auditory thalamus or cortex to the lateral amygdala (LA) underlies the acquisition of auditory fear conditioning. Whereas the mechanisms of postsynaptic LTP at thalamo-LA synapses are well understood, much less is known about the sequence of events mediating presynaptic NMDA receptor-dependent LTP at cortico-LA synapses. Here, we show that presynaptic cortico-LA LTP can be entirely accounted for by a persistent increase in the vesicular release probability. At the molecular level, we found that signaling via the cAMP/PKA pathway is necessary and sufficient for LTP induction. Moreover, by using mice lacking the active-zone protein and PKA target RIM1␣ (RIM1␣ ؊/؊ ), we demonstrate that RIM1␣ is required for both chemically and synaptically induced presynaptic LTP. Further analysis of cortico-LA synaptic transmission in RIM1␣ ؊/؊ mice revealed a deficit in Ca 2؉ -release coupling leading to a lower baseline release probability. Our results reveal the molecular mechanisms underlying the induction of presynaptic LTP at cortico-LA synapses and indicate that RIM1␣-dependent LTP may involve changes in Ca 2؉ -release coupling.fear conditioning ͉ release probability ͉ synaptic plasticity ͉ synaptic transmission A uditory fear conditioning requires the induction of NMDA receptor-dependent long-term potentiation (LTP) in the lateral nucleus of the amygdala (LA) (1-3). Sensory information reaches the LA by two main glutamatergic pathways originating in sensory thalamus and cortex (1). The induction and expression of LTP at thalamo-LA synapses is mediated by Ca 2ϩ influx through postsynaptic NMDA receptors eventually leading to the recruitment of new AMPA receptors to the postsynaptic membrane (4-7). LTP at cortico-LA synapses is mediated by contrasting mechanisms. Pairing of presynaptic stimulation with postsynaptic depolarization triggers LTP that is induced postsynaptically (5, 8-10) and may involve both pre-and postsynaptic expression mechanisms, such as an increase in glutamate release and the recruitment of postsynaptic AMPA receptors (7-10). In contrast, coactivation of the thalamo-and the cortico-LA pathways results in NMDA receptor-dependent LTP that is induced and expressed entirely via presynaptic mechanisms (10, 11). However, the sequence of molecular events underlying presynaptic cortico-LA LTP is poorly understood.At the mossy fiber synapse connecting hippocampal granule cells to CA3 pyramidal cells, presynaptic LTP induction does not require NMDA receptor activation, but involves the Ca 2ϩ -dependent activation of the cAMP/PKA pathway (12, 13). A similar sequence of events has been demonstrated to underlie presynaptic LTP induction at cerebellar parallel fiber synapses, corticothalamic synapses, and parabrachial afferents to the central amygdala (14-16). One of the key PKA targets necessary for presynaptic LTP is the active-zone scaffolding protein RIM1␣ (17-19). RIM1␣ is a multidomain protein th...

“…IL1RAPL1/NCS-1 interaction could be essential for synaptic physiology: Indeed, NCS-1 modulates VGCC activity at synapses thereby controlling short term plasticity (13). In addition, Ca 2ϩ signaling in both synaptic compartments efficiently controls long term plasticity (38,39), thought to be the cellular substrate for learning and memory. Our proposals are in line with the recent progress in the field of MR suggesting that synaptic defects may explain the cognitive impairment resulting from mutations in MR-related genes which products are localized at the pre-and/or postsynaptic compartments (2).…”

Section: Discussionmentioning

confidence: 99%

IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca ²⁺ -channel and neurite elongation

Gambino

Pavlowsky

Béglé

et al. 2007

Self Cite

. The functional relevance of the interaction between IL1RAPL1 and NCS-1 was also suggested by the reduction of neurite elongation observed in nerve growth factor (NGF)-treated IL1RAPL1 cells, a phenotype rescued by NCS-1 inactivation. Because both proteins are highly expressed in neurons, these results suggest that IL1RAPL1-related mental retardation could result from a disruption of N-VGCC and/or NCS-1-dependent synaptic and neuronal activities.PC12 cells ͉ neuronal calcium sensor-1 ͉ X-linked mental retardation ͉ exocytosis C ognitive impairment or mental retardation (MR) affects Ϸ2% of the population, leading to moderate (IQ Ͻ70) up to severe (IQ Ͻ50) handicap. The underlying causes are extremely heterogeneous, including genetic causes, many of which are X-linked (XLMR) (1, 2). Null mutations in the IL1-receptor accessory protein-like 1 gene (IL1RAPL1) [National Center for Biotechnology Information (NCBI) accession no. NM 014271.2] have been involved in a nonsyndromic form of XLMR (3). IL1RAPL1 and the closely related protein IL1RAPL2 (NCBI accession no. NM 017416) belong to a previously unrecognized class of the interleukin-1/toll receptor family characterized by the presence of a 150-aa C terminus domain with unknown function (3, 4). IL1RAPL1 and IL1RAPL2 have specific, but not redundant, temporal and spatial expression pattern in the brain, Il1rapl1, the mouse homologue of IL1RAPL1, being specifically expressed in adult brain structures that are known to be involved in the hippocampal memory system (3).Most of physiological and biological properties of IL1RAPL proteins remain largely unknown. Recent studies have demonstrated that expression of IL1RAPL1 in PC12 cells leads to a profound inhibition of ATP-induced growth hormone (GH) release (4). The underlying cellular pathways remain to be elucidated; however, IL1RAPL1 has been shown to interact by way of its 150-aa C-terminal domain with the neuronal calcium sensor-1 protein (NCS-1), a protein widely expressed in neurons (5) and the related chromaffin and PC12 cells (6).NCS-1 belongs to a large Ca 2ϩ -binding protein family (7) implicated in the regulation of Ca 2ϩ -dependent exocytosis (6) through its activation of PI 4 kinase and PIP 2 formation (8-10). Moreover, NCS-1 modulates Ca 2ϩ channels trafficking and activity in various cellular models (11, 12) and has effects on synaptic transmission by way of activity-dependent facilitation of P/Q-type calcium currents at presynaptic nerve terminals (13). Finally, at the behavioral level, NCS-1 appears also to be involved in associative learning and memory (14).Here, we focus on IL1RAPL1 functions by studying the physiological impact of IL1RAPL1/NCS-1 interaction in PC12 cells, a well known model of both nerve growth factor (NGF)-induced neuronal differentiation and Ca 2ϩ -dependent exocytosis. We show that expression of IL1RAPL1 in PC12 cells, which do not normally express the IL1RAPL1 protein, mediates, through IL1RAPL1/NSC-1 interaction, a down-regulation of N-type voltage-gated calcium channel (N-VGCC) ac...