Much more work is needed to determine the physiological impact of these heteromeric complexes

in the brain and, in particular, at the synapse. In addition to triggering various forms of synaptic plasticity like DSI/DSE, eCB-LTD, and TRPV1-LTD, the eCB system itself undergoes plastic changes. Mechanistically, plasticity of the eCB system can arise by modifications to any of its components, for example, CB1R number and function TGF-beta inhibitor or eCB production and degradation. These changes have been observed both in vivo and in vitro and can be triggered by several natural and experimental conditions including neural activity and agonist-induced CB1R activation. Of clinical relevance, changes in eCB signaling are also associated with several brain disorders. Here, we illustrate how plasticity of the eCB system can profoundly affect synaptic physiology and, ultimately, brain function. An interesting example of agonist-induced plasticity of eCB signaling comes from the observation that a single in vivo exposure to THC abolished for a few days eCB-mediated retrograde

signaling in the hippocampus and nucleus accumbens of mice (Mato et al., 2004). This effect was associated with a reduction in CB1R maximal find more efficacy without modifications in total binding or coupling. Prolonged exposure to agonists in humans and animal models results in behavioral tolerance, which is classically attributed to receptor desensitization and internalization (Coutts et al., 2001; Jin et al., 1999; Wu et al., 2008). However, a reduction in CB1R lateral mobility may also contribute L-NAME HCl (Mikasova et al., 2008). Understanding the impact of synaptic CB1R signaling and trafficking in vivo should further reveal how eCBs control physiological responses to drugs of abuse. The eCB system also undergoes developmental changes (Harkany et al., 2008). In the hippocampus, both the magnitude of eCB-mediated iLTD and the ability of a CB1R agonist to suppress inhibitory transmission were greater in juvenile than in adult rats (Kang-Park et al., 2007; see also Zhu and Lovinger, 2010). In addition, a form of eCB-mediated heterosynaptic LTD at excitatory

synapses was observed in young animals, attenuated across development, and disappeared in the mature brain (Yasuda et al., 2008). Lower expression levels of CB1Rs at excitatory synapses in the adult brain may underlie these changes (Kawamura et al., 2006). Along these lines, developmentally expressed CB1Rs at mossy fiber terminals in the CA3 region of the hippocampus mediate eCB-LTD at immature but not mature synapses (Caiati et al., 2012). Postsynaptic eCB production is also modulated over time. A developmental shift from long-term potentiation (LTP) to eCB-LTD was reported in the striatum (Ade and Lovinger, 2007). Whereas CB1R sensitivity to its agonist was not changed, the shift in plasticity was associated with developmental increases in AEA levels, suggesting that AEA determines the direction of synaptic plasticity.