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Figure 3 and also in recent review [14]. Phospholipase C (PLC)-mediated hydrolysis of
membrane phospholipids may produce diacylglycerol (DAG), which may be subsequently
converted to 2-AG by diacylglycerol lipase (DAGL) activity [169, 187]. The formation of
DAG also involves the hydrolysis of phosphatidic acid through Mg 2+ and Ca 2+ -dependent PA
phsophohydrolase activity [25, 36]. Alternatively, phospholipase A1 (PLA1) may generate a
lysophospholipid, which may be hydrolyzed to 2-AG by lyso-PLC activity [187]. Under
certain conditions, 2-AG can also be synthesized through the conversion of 2-arachidonyl
lysophosphatidic acid (LPA) by phosphatase to yield 2-AG [152]. Molecular characterization
of these potential pathways remains to be accomplished. 2-AG, like AEA, is found in a
variety of tissues throughout the body and brain, and appears to be released from cells in
response to certain stimuli. 2-AG activates the CB1 receptor with greater efficacy than does
AEA. 2-AG is inactivated by reuptake [22, 24] via uncharacterized membrane transport
molecule, the 'AEA membrane transporter' (AMT) [20, 22, 23, 75, 93, 94, 124], and
subsequent intracellular enzymatic degradation [53, 56, 61] by monoacylglycerol (MAGL)
lipase (Fig. 6), like other monoacylglycerols [114]. Similarly, 2-AG is metabolized by MAGL
lipase from porcine brain cytosol and particulate fractions [80]. Interestingly, MAGL is
expressed in presynaptic terminals [64, 81], suggesting it has a role in terminating EC
signaling at presynaptic neurons [185]. 2-AG is metabolized to 2-arachidonyl LPA through
the action of monoacyl glycerol kinase(s). 2-Arachidonyl LPA is then converted into 1-
steroyl-2-arachidonyl PA [178]. 1-steroyl-2-arachidonyl PA is further utilized in the “PI
cycle” or is used in the de novo synthesis of PC and PE. Furthermore, 2-AG is metabolized
by enzymatic oxygenation of 2-AG by COX-2 into PGH2 glycerol esters. The biological
activity and the role of oxygenated 2-AG are yet to be determined.
2.3 Synaptic Plasticity
Changes in the strength and number of synaptic connections between neurons are
believed to be one of the major mechanisms underlying learning and memory and mediating
other physiological functions of the CNS. This phenomenon is called synaptic plasticity. This
characteristic is present both during brain development and in the adult life. In its most
general form, the synaptic plasticity and memory hypothesis states that "activity-dependent
synaptic plasticity is induced at appropriate synapses during memory formation and is both
necessary and sufficient for the information storage underlying the type of memory mediated
by the brain area in which that plasticity is observed." Several key molecules are involved in
normal synaptic formation [5-7, 38, 47, 109, 126, 132-134, 154], but their interactions are not
well understood. There are various forms of synaptic plasticity differing with respect to their
persistence over time and their underlying induction and expression mechanisms. Table 1
gives an overview of different mechanisms, their time scales and synaptic location.
2.3.1 Short-term synaptic plasticity
Synaptic transmission is subject to a wide range of short-term changes in synaptic
strength, termed short-term synaptic plasticity. Short-term synaptic plasticity enables neurons
to not just relay but rather, to actively transform their inputs to produce a patterned output.
The differences in short term synaptic plasticity among neurons, and in particular the
differences between excitatory and inhibitory neurons, are important for information
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