Temporal Gating of Synaptic Competition in the Amygdala by Cannabinoid Receptor Activation

Madeira, Natália; Drumond, Ana; Fonseca, Rosalina

doi:10.1093/cercor/bhaa026

Cited by 11 publications

(13 citation statements)

References 44 publications

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“…By suspending ongoing synaptic activation, we were able to prolong the time window of cooperation reverting the effect of Cdc42 inhibition. We have also observed this modulatory effect of synaptic activity in the time window of synaptic cooperation in the amygdala circuitry (Fonseca, 2013;Madeira et al, 2020), showing that excitatory synapses of pyramidal neurons have similar temporal dynamics. The blockade of Cdc42 inhibition in synaptic cooperation was also reverted by promoting actin depolymerization, suggesting that increasing G-actin availability is able to counteract the inhibition of Cdc42.…”

Section: Discussionsupporting

confidence: 56%

“…One interesting aspect of heterosynaptic competition is the observation that its induction depends on the order and the temporal relationship between activated synaptic inputs (Madeira et al, 2020). To illustrate this temporal rule, we plotted the percentage decay for each activated input, Weak1, Weak2 and Strong in relation to the percentage potentiation of each input and found statistically significant correlations between sequentially activated inputs (Figure 3F).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, comprehending the nature of the tag and its dynamics is crucial to understanding the time frame of such heterosynaptic interactions and ultimately how these mechanisms contribute to memory acquisition. We have previously proposed that the tag, rather than a specific molecule, is a state of the synapse that in an activity and time-dependent manner renders synapses permissive to change (Madeira et al, 2020; Pinho et al, 2020; Szabó et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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Cdc42 activation is necessary for heterosynaptic cooperation and competition

Nunes,

Madeira,

Fonseca

2023

Preprint

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Synapses change their weights in response to neuronal activity and in turn, neuronal networks alter their response properties and ultimately allow the brain to store information as memories. As for memories, not all events are maintained over time. Maintenance of synaptic plasticity depends on the interplay between functional changes at synapses and the synthesis of plasticity-related proteins that are involved in stabilizing the initial functional changes. Different forms of synaptic plasticity coexist in time and across the neuronal dendritic area. Thus, homosynaptic plasticity refers to activity-dependent synaptic modifications that are input-specific, whereas heterosynaptic plasticity relates to changes in non-activated synapses. Heterosynaptic forms of plasticity, such as synaptic cooperation and competition allow neurons to integrate events that occur separated by relatively large time windows, up to one hour. Here, we show that activation of Cdc42, a Rho GTPase that regulates actin cytoskeleton dynamics, is necessary for the maintenance of long-term potentiation (LTP) in a time-dependent manner. Inhibiting Cdc42 activation does not alter the time-course of LTP induction and its initial expression but blocks its late maintenance. We show that Cdc42 activation is involved in the phosphorylation of cofilin, a protein involved in modulating actin filaments and that weak and strong synaptic activation leads to similar levels on cofilin phosphorylation, despite different levels of LTP expression. We show that Cdc42 activation is required for synapses to interact by cooperation or competition, supporting the hypothesis that modulation of the actin cytoskeleton provides an activity-dependent and time-restricted permissive state of synapses allowing synaptic plasticity to occur. We found that under competition, the sequence in which synapses are activated determines the degree of LTP destabilization, demonstrating that competition is an active destabilization process. Taken together, we show that a dynamic actin cytoskeleton is necessary for the expression of homosynaptic and heterosynaptic forms of plasticity. Determining the temporal and spatial rules that determine whether synapses cooperate or compete will allow us to understand how memories are associated.Graphical AbstractHighlightsCdc42 is required for the maintenance of homosynaptic synaptic plasticityWeak and strong stimulation modulate actin by cofilin phosphorylationCdc42 activation is necessary for heterosynaptic cooperation and competitionSynaptic competition is an active destabilization processThe time-window of synaptic cooperation and competition is activity dependent

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Section: Discussionsupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cdc42 activation is necessary for heterosynaptic cooperation and competition

Nunes,

Madeira,

Fonseca

2023

Preprint

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“…At the synaptic level, competition was induced by the temporally related stimulation of three inputs to the LA (one cortical, two thalamic) 24 . Given that neurons in the MGm thalamic nuclei have a multimodal response, including visual stimuli, we added a third event in which animals are exposed to a third, different context and visual stimuli (green flashing led).…”

Section: Memory Competition Is Dependent On Time and Order Of Eventsmentioning

confidence: 99%

Temporal rules of fear memory cooperation and competition

Madeira,

Campelo,

Fonseca

2024

Preprint

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Memory consolidation is highly influenced by ongoing experiences. We explore the temporal rules that determine whether events are cooperatively associated or competitively separated. We show that neutral events are associated with fearful events if they occur within less than 30 minutes. In some individuals, memory association can lead to a competitive suppression of the fearful response by the neutral event. Activation of the thalamic MGm inputs to the lateral amygdala, led to an increase in memory association, whereas manipulation of the cortical inputs had no effect. Introducing a third event leads to competition depending on the temporal relationship between the initial association and the competitive event. Our results show a critical temporal rule of memory association, modulated by thalamic activity that shapes fear memory consolidation.

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“…Retrograde eCB signaling mediates both short-term (Kreitzer and Regehr, 2001; Ohno-Shosaku et al, 2001; Wilson and Nicoll, 2001) and long-term synaptic plasticity throughout the brain (Chevaleyre and Castillo, 2003; Gerdeman et al, 2002; Marsicano et al, 2002; Robbe et al, 2002). Furthermore, CB1 has influence as a temporal window component for synaptic plasticity in the amygdala (Fonseca, 2013; Madeira et al, 2020).…”

mentioning

confidence: 99%

A Cannabinoid Receptor 1 Agonist Reduces Light-induced Phase Delays in Male But Not Female Mice

Niepokny

Mintz

2023

J Biol Rhythms

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Animals adapt to a changing environment by synchronizing their circadian rhythms to different stimuli, the strongest and most reliable being the daily light-dark cycle. Photic information reaches the central circadian pacemaker, the suprachiasmatic nucleus (SCN), which drives rhythms in physiology and behavior throughout the brain and body. The endocannabinoid system (ECS) is a neuromodulatory system that is present within the SCN, including the primary receptor, cannabinoid receptor 1 (CB1). Exogenous cannabinoids that target CB1 inhibit the phase-shifting effects of light in hamsters, mice, and rats. Furthermore, there is evidence in cultured microglial cells that cannabidiol (CBD), a constituent of Cannabis sativa, alters core circadian clock genes, while the CB1 agonist delta-9-tetrahydrocannabinol (THC) does not. The CB1 agonist studies were conducted using male animals only, but cannabinoids exhibit sex-dependent effects in various aspects of physiology and behavior. In addition, the effects of CBD on circadian behavioral rhythms have yet to be investigated. Therefore, we decided to test the effects of acute injections of CBD or the CB1 agonist CP 55,940 on light-induced phase delays in male and female C57BL/6J mice. Animals received a single injection at circadian time (CT) 15.5, followed by a 10-min light or dark (sham) pulse at CT 16. Running-wheel activity was monitored to determine activity levels and the behavioral phase shifts from different treatments. We observed a sex difference in the magnitude of phase delay size in response to CP 55,940 administration. Males had attenuated phase delays with increasing doses of CP 55,940, while females did not differ from control. Various doses of CBD had no effect on the phase-delaying effects of light in either sex. Our results show a sex difference in the gating of photic phase shifts by CB1 activation.

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Temporal Gating of Synaptic Competition in the Amygdala by Cannabinoid Receptor Activation

Cited by 11 publications

References 44 publications

Cdc42 activation is necessary for heterosynaptic cooperation and competition

Cdc42 activation is necessary for heterosynaptic cooperation and competition

Temporal rules of fear memory cooperation and competition

A Cannabinoid Receptor 1 Agonist Reduces Light-induced Phase Delays in Male But Not Female Mice

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