Circuitry for Associative Plasticity in the Amygdala Involves Endocannabinoid Signaling

“Similarly, priming-stimulation-induced iLTD facilitates LTP that is induced at least 60–90 minutes late”

“Moreover, pharmacological blockade of CB1 receptors led to a similar deficit in wild-type mice (16), which was ameliorated with administration of a CCK2 receptor antagonist (72).”

“A candidate mechanism for the acute changes could be a form of inhibitory long-term depression (LTDi) observed in BLA slices, which is CB1 receptor-dependent and mediated by a decrease in presynaptic GABA release (Azad et al., 2004; Marsicano et al., 2002).”

“For instance, electrophysiological and biochemical evidence shows that 2-AG is mostly involved in retrograde control of synaptic activity in the VTA (109), or the hippocampus (112), whereas AEA appears to play an important role in other regions, such as the basal ganglia (113) and the amygdala (114).”

“, but, occasionally, mGluR 1 activates the signalin”

“The release of anandamide and concomitant CB1-receptor activation induce long-term depression of inhibitory transmission (LTDi) in the BLA (Azad et al., 2004; Gunduz-Cinar et al., 2013b).”

“The postsynaptic mechanisms responsible for triggering eCB-LTD are not well understood, although activation of metabotropic glutamate receptors (mGluRs) is required in the hippocampus, striatum, and amygdala (Sung et al., 2001; Robbe et al., 2002b; Chevaleyre and Castillo, 2003; Azad et al., 2004).”

“Specifically, AEA signaling within the amygdala mediates forms of synaptic plasticity, such as inhibitory long-term depression, which are conducive to fear extinction and emotional flexibility (Azad et al., 2004).”

“[99] have shown that CB1 receptors reduce GABA-ergic synaptic transmission in the amygdale, and consequently facilitate extinction of aversive memories.”

“CB1 receptors are localized on inhibitory interneurons in the amygdala (Azad et al., 2004) and may regulate the activity of these neurons during extinction learning (Chhatwal et al., 2005a; Chhatwal et al., 2009).”

“The effect was potentiated by blocking anandamide degradation, implying that this eCB, rather than 2-AG, is involved (Azad et al., 2004).”

“Second, animal studies have demonstrated that exogenous and endogenous cannabinoids can significantly alter synaptic transmission in the nucleus accumbens (Lupica et al., 2004) and in the amygdala (Azad et al., 2004).”

“Furthermore, we tested the generality of these mechanisms in the basolateral amygdala (BLA) where eCBs mediate I-LTD (Azad et al., 2004;Marsicano et al., 2002).”

“for EC-LTD in amygdala (Azad et al. 2004), or if these signaling mechanisms are involved in presynaptic EC-LTD maintenance.”

“…of dopamine signaling and long-term synaptic plasticity in the striatum (Giuffrida et al, 1999; Beltramo et al, 2000; Gerdeman et al, 2002; Azad et al, 2004) as well as acetylcholine signaling in the neocortex and hippocampus (Gifford et al, 1999; Tzavara et al, 2003; Steffens et al,…”

“One notable finding is that a CB1R-dependent form of synaptic plasticity in BLA [51,86], long-term depression of inhibitory GABAergic transmission (LTDi), is enhanced by FAAH KO [51] and by the FAAH inhibitor AM3506 at doses that promote extinction [50].”

“The same may be true in the lateral amygdala, where CB1 receptor-activation may inhibit both GABA and glutamate release (Azad et al. 2003; 2004).”

“eCB-mediated I-LTD has been identified in the hippocampus [9], amygdala [10,11], dorsal striatum [12], brainstem [13] and visual cortex [14 ].”

“There are, however, several forms of endocannabinoid-mediated plasticity that do not require Ca(2) for their expression, such as those triggered by muscarinic acetylcholine receptors in the hippocampus (Maejima et al., 2001; Kim et al., 2002; Chevaleyre and Castillo, 2003; Azad et al., 2004; Galante and Diana, 2004).”

“In contrast, preLTP at thalamic inputs onto local amygdala inhibitory interneurons is linked with fear suppression (Bauer & LeDoux 2004), whereas fear extinction in the amygdala appears to involve eCB-mediated iLTD (Lutz 2007, Azad et al. 2004).”

“Several studies have reported strong inhibition of BLA interneurons after application of CB1 receptor agonists (Azad et al., 2004; Pistis et al., 2004), which is expected to decrease local inhibitory feedback on pyramidal amygdalar outputs neurons.”

“, 2007), amygdala (Marsicano et al., 2002; Azad et al., 2004), and nucleus accumbens (Robbe et al.”

“It is also not because of a general impairment in 2-AG signaling because receptor-driven eCB release initiated by 50 mM dihydroxyphenylglycine (B50% eIPSC suppression) is comparable to that observed in BLA and other brain regions (Patel and Winder, unpublished data; (Azad et al, 2004)).”

“the extinction of aversive memories, is enhanced in FAAH KO mice (Azad et al., 2004).”

“By using brain slices, HFS of lateral amygdala induces LTD of GABAergic transmission in the BLA, which then increased amplitudes of EPSCs in the neurons of the CeA, the final output nuclei from the amygdala (Azad et al., 2004).”

“Some of these are: Neuronal plasticity [6], pain [7], anxiety [8], inflammation [9], neuro-inflammation [10], immune function [11], metabolic regulation [12], and bone growth [13].”

“Endocannabinoids also exert an amnesic effect and are crucial for the extinction (forgetting) of aversive memories (91, 92), while blockade of the CB1 receptor induces deficits on the extinction of aversive memories and supersensitivity to stress (74).”

“Thus, similar to the hippocampus (Chevaleyre and Castillo, 2003) and amygdala (Azad et al., 2004), I-LTD in the PFC does not require postsynaptic calcium increases, further bolstering the idea that postsynaptic D2Rs are not involved.”

“[19] showed that low-frequency stimulation of afferents in the lateral amygdala released endocannabinoids postsynaptically from neurons of the basolateral amygdala of mice, and thereby induced an LTP of inhibitory GABAergic synaptic transmission (LTDi) via a presynaptic mechanism.”

“However, long-term depression in the amygdala was stronger in mice lacking fatty acid amide hydrolase and not changed by U73122 and RHC80267 – findings pointing to a role of anandamide (Azad et al. 2004).”

“, 2009a), emerging evidence indicates that specific forms of phasic and tonic endocannabinoid signaling at given brain circuit locations or under specific physiological conditions are mediated by anandamide (Azad et al., 2004; Kim and Alger, 2010; Huang and Woolley, 2012; Lerner and Kreitzer, 2012; Khlaifia et al., 20…”

“More specifically, the endogenous cannabinoid anandamide could decrease the inhibitory activity of interneurons in the amygdala (Azad et al. 2004).”

“Alternately, cAMP-protein kinase signaling has been found to promote AEA synthesis in neuronal cultures and slice preparations (Azad et al., 2004; Cadas et al., 1996; Malcher-Lopes et al., 2006; Vellani et al., 2008) and voluntary exercise is known to increase hippocampal cAMP signaling (Shen et…”

“Activation of CB1 receptors on theGABAergic neurons leads to a decrease inGABA release (20, 48) and thus to formation of the depolarization-induced suppression of inhibition (DSI) (35) and long-term depression of inhibitory GABAergic synaptic transmission (LTDi) (49, 50).”

“As LTDi in the BLA has been demonstrated to involve group-1 metabotropic glutamate receptors (mGluR; Azad et al, 2004), we pretreated slices with a combination of mGluR1 and mGluR5 antagonists (LY456236 (10 mM) and MTEP (10 mM), respectively).”

“This mGluR-dependent component of DSI may be similar to endocannabinoiddependent long-term depression (LTD) (Gerdeman et al., 2002; Robbe et al., 2002; Chevaleyre and Castillo, 2003; Azad et al., 2004), but additional studies examining the duration of this synaptic depression will be needed to determine whether this i…”

“, in amygdala [21, 100, 101], hippocampus [101–104], and prefrontal areas [105].”

“Retrograde endocannabinoid signalling mediated through the CNR1 has been suggested as a possible mechanism for extinction of aversive memories (Azad et al., 2004; Cannich et al., 2004).”

“Endocannabinoids act as retrograde messengers mediating CB1-dependent forms of short-term synaptic plasticity known as depolarization-induced suppression of inhibition or excitation (Diana and Marty, 2004) and longer-lasting forms of synaptic plasticity, such as long-term depression (Gerdeman and Lovinger, 2001; Robbe…”

“Endocannabinoids exert an amnesic effect and may be crucial for the extinction of aversive memories,([76,77]) while blockage or knockout of the CB1 receptor induce deficits of the extinction processes and supersensitivity to stress([78]) by decreasing GABAergic function.”

“Postsynaptic release and retrograde diffusion of endocannabinoids results in presynaptic CB1R activation and suppression of neurotransmitter release from presynaptic [20,26-31] and, indirectly, from postsynaptic terminals [32].”

“Both amygdala synaptic plasticity and learned fear aremodulatedbyanumberof factors, including neuromodulators (Rosenkranz and Grace, 2002; Azad et al., 2004), steroid hormones (Setlow et al., 2000) and level of GABAergic inhibition (Watanabe et al., 1995; Rammes et al., 2000).”

“Both responses reflect mGluR5-dependent eCB-mediated alteration in synaptic GABA release (Azad et al., 2004; Marsicano et al., 2002) and were blocked by pretreatment with the CB1R antagonist AM251 (Figures 3B and 3C).”

“…by CB1 receptors signaling on both inhibitory and excitatory amygdalar neurotransmissions has been recently associated with the temporal adaptation of conditioned freezing responses (Kamprath et al., 2011) and in the control of synaptic plasticity (Marsicano et al., 2002; Azad et al., 2004).”

“…et al. 2005; Mascagni and McDonald 2007; Muller et al. 2007) and are thought to mediate specific aspects of fear memoryrelated information processing within the amygdala (e.g., Quirk et al. 2003; Azad et al. 2004; Marowsky et al. 2005) and hippocampus (Crestani et al. 1999; Gafford et al. 2005).”

“, hippocampus [120-122], PFC [123] and amygdala [124-127]) and that have been ascribed to an adverse impact of cannabinoids on the cerebellum [128].”

“[33] Azad SC, Monory K, Marsicano G, Cravatt BF, Lutz B, Zieglgansberger W, et al.”

“On the other hand, estradiol affects synaptic plasticity in the hippocampus via a CB1R-AEA mediated mechanism (65) and AEA mediates a form of long-term depression in the amygdala (2), indicating that there are some circumstances under which AEA is the primary endogenous activator of synaptic CB1R.”

“This process may be related to structural changes within the basolateral nucleus of the amygdala, as eCBs have been shown to regulate synaptic plasticity in this structure, likely affecting emotionality (Azad et al. 2004; Kodirov et al. 2009; Marsicano et al. 2002).”

“, 2010) and have determined that this process is reliant on mGluR1 receptor function (Azad et al., 2004).”

“…BLA neuronal population would be expected to increase local inhibitory feedback on BLA projection neurons, as suggested by other neuronal recording studies that have observed strong inhibition of BLA interneurons after application of CB1 receptor agonists (Azad et al., 2004; Pistis et al., 2004).”

“To account for their results, Azad et al. (2004) propose that release of AEA might be a dynamically regulated step.”

“Furthermore, lowfrequency stimulation of afferents in this amygdala subregion induces a release of AEA postsynaptically from BLA neurons, thereby inducing long-term depression of GABAergic synaptic transmission via a CB1 receptor-dependent presynaptic mechanism (Azad et al., 2004).”

“…plasticity has been described in several brain regions such as hippocampus (Chevaleyre and Castillo, 2003), amygdala (Marsicano et al., 2002; Azad et al., 2004), striatum (Adermark and Lovinger, 2009), visual cortex (Jiang et al., 2010) and cerebellum (Pitler and Alger, 1992; Llano et al.,…”

“demonstrated a role for CB1 receptor transmission during the processing of neuronal plasticity and emotional associative learning behaviors within this neural circuit (Azad et al. 2004; Laviolette and Grace 2006b; Roche et al. 2007).”

“Several lines of evidence support the view that mGluR and cAMP mediated pathways functionally interact in platelets [26], lymphocytes [27], neurons [28–32] and astrocytes [33].”

“In the amygdala, however, endocannabinoid-mediated plastic changes have been shown to involve AEA release through activation of a cyclic adenosine monophosphate-protein kinase A (cAMP-PKA)-dependent pathway (Azad et al, 2004).”

“of the brain, including the striatum [62], hippocampus [63-68], midbrain [69], and amygdala [70,71].”

“[14] has provided evidence that mGluR1 activation in inhibitory neurons in the basolateral amygdala induces activation of endocannabinoid signaling which is required for fear extinction.”

“In contrast, in the amygdala, endocannabinoid-mediated long-term depression of inhibitory GABAergic synaptic transmission is enhanced in FAAH / mice (Azad et al., 2004), whereas in other systems, 2-AG may be more important (Melis et al., 2004; Makara et al., 2004).”

“Endocannabinoid LTDi in the BLA in turn, enhances excitatory synaptic transmission in the CeA [2].”

“Given previous findings that group I mGluR agonists can trigger eCB release and induce LTD in several brain structures (Azad et al., 2004; Neuropharmacology.”

“High levels of CB1 receptors are localized in the BLA region of the amygdala (2, 6) and CB1 transmission within the BLA is involved in the regulation of associative learning and memory processing (50, 51).”

“This finding is in line with data from the hippocampus and basolateral amygdala indicating that glutamatergic synaptic activation of group I mGluRs is critical for afferent stimulus-induced LTD at inhibitory synapses (Azad et al., 2004; Chevaleyre and Castillo, 2003).”

“Interestingly, a form of endocannabinoid-mediated amygdalar heterosynaptic LTD [60] was triggered using a low-frequency stimulation (1 Hz) not too dissimilar to the frequencies (2 Hz) adopted by Branco et al.”