Alterations in the efficacy of synaptic transmission are believed to be cellular mechanisms of learning and memory. Two well-studied forms of such synaptic plasticity are long-term potentiation (LTP) and long-term depression (LTD), which have been widely observed at different types of synapses in many brain areas (Citri and Malenka, 2008). The signaling mechanisms of synaptic plasticity vary to some extent depending on the types of synapses and stimulation. One of the main differences is the synaptic site of expression: some forms of LTP and LTD rely on changes in presynaptic neurotransmitter release, but others rely on changes in postsynaptic receptor numbers or properties (Malenka and Bear, 2004; Castillo, 2012; Huganir and Nicoll, 2013). Nevertheless, there are some properties shared by several forms of LTP and LTD. A common property of all forms of LTP and LTD is that potentiation and depression are triggered by transient stimulation, whereas the potentiation and depression last for a long time. For the long-term maintenance of altered synaptic strength, translational, and transcriptional regulations are often involved (Citri and Malenka, 2008). The protocol triggering LTP or LTD usually consists of strong or repeated synaptic stimulation, which likely activates synaptic receptors and triggers increases in the levels of signaling molecules, such as calcium and diacylglycerol (DAG). In fact, signaling mechanisms associated with calcium or DAG have been shown to be required for several forms of LTP and LTD (Sossin and Farah, 2009).

In many types of cells, including neurons, DAG is generally produced after the activation of G-protein coupled receptors (GPCRs) through the metabolization of phosphatidylinositol 4,5-bisphosphate by phospholipase C (PLC) (Rhee, 2001). At synapses, an increase in DAG level by the activation of GPCRs likely regulates its target molecules required for synaptic plasticity (Brose et al., 2004). A well-known target molecule of DAG is protein kinase C (PKC), which has been shown to be involved in many forms of LTP or LTD. Therefore, the regulation of DAG concentrations at synapses is crucial for the regulation of these forms of LTP or LTD.

The conversion of DAG to phosphatidic acid (PA) by diacylglycerol kinase (DGK) is the major pathway for the termination of DAG signaling (Sakane et al., 2007). Ten mammalian DGK isoforms have been identified so far, and at least 8 of them are readily detected in the mammalian brain, suggesting the important roles of DGKs in the brain (Tu-Sekine and Raben, 2011). Interestingly, the expression pattern of each isoform in the brain is different, and their subcellular localizations are distinct (Tu-Sekine and Raben, 2011; Ishisaka and Hara, 2014), suggesting that different isoforms of DGKs have unique neuronal or synaptic functions. In this review, we summarize the roles of DGKs in the regulation of synaptic plasticity (see Table 1 for summary), focusing on specific types of synaptic plasticity and individual DGK isoforms involved. In addition, we would like to emphasize the emerging notion that DGKs may be involved in the generation of local environments suitable for synaptic plasticity.

In addition to hippocampal synaptic plasticity, DGKζ regulates cerebellar LTD that is postsynaptically expressed at the synapses of cerebellar Purkinje cells receiving inputs from parallel fibers, as supported by impaired LTD, but not LTP, in DGKζ^−/− mice (Lee et al., 2015). Cerebellar LTD has long been studied, and the importance of PKC in LTD has also been well established (Linden and Connor, 1991; De Zeeuw et al., 1998), with the PKC isoform PKCα being critical (Leitges et al., 2004). Our results showed that DGKζ bound to not only PSD-93, a PSD-95 relative abundant in Purkinje cells, but also to PKCα in Purkinje cells, and such binding functions of DGKζ were required for LTD (Lee et al., 2015). In addition, we have shown that LTD induction causes the dissociation of DGKζ and PKCα, and that the catalytic function of DGKζ is also required for LTD. These results collectively suggest the following mechanisms. PSD-93-bound DGKζ interacts with and promotes the synaptic localization of PKCα, but suppresses PKCα activity under basal conditions by reducing DAG concentrations. When LTD is triggered, PKCα dissociates from DGKζ and gets activated to promote the induction of cerebellar LTD.

As summarized above, 5 different isoforms of mammalian DGKs have so far been reported to be involved in some forms of synaptic plasticity (Table 1). Generally, the 10 known isoforms of DGKs are categorized into five types based on their distinct functional domain structures, which display differential distribution patterns in the brain (Ishisaka and Hara, 2014). These diversities in the domain structures and distribution patterns of brain DGKs may influence their distinct subcellular localization, spectrum of binding proteins, and regulation of specific aspects of LTP and LTD.

Although, the current results suggest that individual DGK isoforms distinctly regulate several forms of LTP or LTD, they can be considered to play a conceptually common role in synaptic plasticity. In general, molecules involved in synaptic plasticity fall into two categories based on their functions, namely, mediators or modulators. Mediators are directly responsible for triggering synaptic plasticity, whereas modulators are molecules modulating the ability to trigger synaptic plasticity or playing a permissive role (Citri and Malenka, 2008). Given that all isoforms of DGKs described above do not directly mediate the expression of synaptic plasticity, they should be categorized as modulators. Furthermore, DGKs may be specifically considered as coordinators because they function to prepare synapses to undergo synaptic plasticity. As described above, in some cases, DGKs reduce DAG signaling under basal conditions so that DAG signaling can be effectively enhanced after the induction of synaptic plasticity. In other cases, DGKs control DAG signaling “after” the initiation of the induction of synaptic plasticity. Therefore, DGK-dependent modulation of DAG tones before and after the induction of synaptic plasticity may create synaptic environments appropriate for triggering synaptic plasticity. Such a coordinating role would be accomplished by the ability of DGKs to localize itself at synapses, to bind, recruit, and temporally suppress the activity of downstream effector molecules of DAG, such as PKCα, required for synaptic plasticity, and to timely terminate DAG signaling to suppress excessive induction of synaptic plasticity (Figure 1).

Studies using knockout mice of specific isoforms of DGKs have demonstrated the involvement of DGKs in some forms of synaptic plasticity, and based on these studies, the general role of DGKs in synaptic plasticity has been proposed. The next question that naturally arises is whether other DGK isoforms that are abundantly expressed in the brain, such as DGKα, DGKγ, DGKη, and DGKθ, also play roles in some forms of synaptic plasticity. Future studies to address this question should support or even strengthen the idea that DGKs function as coordinators of synaptic plasticity.

Although, we have described some molecular mechanisms as to how DGK isoforms are involved in synaptic plasticity, there are still several questions regarding the molecular mechanisms, including the two following straightforward ones. The first is why there are three isoforms of DGKs–DGKβ, DGKζ, and DGKκ–that are required for the regulation of synaptic plasticity in hippocampal CA1 synapses. One possibility is that they play distinct roles based on their specific subcellular localizations and catalytic properties: DGKζ localized at synapses via binding with PSD-95 (Kim et al., 2009) may metabolize only high concentrations of DAG produced after synaptic stimulation, while DGKβ and DGKκ may be capable of metabolizing low concentrations of DAG around synapses (Figure 1). Although, the subcellular localization of DGKκ in neurons still remains unclear, the reported specific localization of DGKβ at the plasma membrane (Caricasole et al., 2002) may render distinct functions to DGKκ and DGKβ under basal conditions.

The second question is how DGK isoforms are localized to presynaptic terminals to regulate presynaptically expressed synaptic plasticity. DGKι is shown to be involved in presynaptic LTD (Yang et al., 2011). Although, the involvement of DGKθ in synaptic plasticity is not directly tested, DGKθ was shown to regulate synaptic vesicle recycling presumably via the production of PA (Goldschmidt et al., 2016). Except for common structural domains of DGKs (C1 and catalytic domains) DGKι and DGKθ do not share domains that may mediate the interaction with presynaptic molecules. Identification of such mechanisms would further advance our understanding of the DGK-dependent regulation of presynaptically expressed synaptic plasticity.

Considering that DGKs create synaptic environments appropriate for triggering synaptic plasticity, DGKs may be adequate regulators of metaplasticity. Metaplasticity refers to activity-dependent synaptic changes that modulate the ability to induce subsequent synaptic plasticity (Abraham and Bear, 1996). The activities of DGKs likely rely on their localization or posttranslational modifications (Shulga et al., 2011), and DGK protein levels may also alter the overall activity of DAG metabolism. Therefore, it is possible that activity-dependent regulation of DGK protein levels, localization, or modification leads to metaplasticity. Intriguingly, it has recently been shown that the cellular microRNA miR-34a targets DGKζ mRNA, and DGKζ expression was decreased via the stimulation-dependent upregulation of miR-34a in immune cells (Shin et al., 2013). A similar regulation of DGKζ or other DGK isoforms may be achieved at synapses as mechanisms of metaplasticity.

Finally, it has not yet been intensively investigated as to how DGK-dependent regulation of synaptic plasticity contributes to learning and memory, although a study has shown that DGKβ is necessary for hippocampus-dependent spatial reference memory formation (Shirai et al., 2010), for which LTP at CA1 synapses is implicated (Martin et al., 2000). To avoid compensation by other DGKs or other mechanisms in knockout mice, it would be needed to employee additional approaches such as conditional knockout of DGKs, mutations in specific domains, or temporal control of such modifications. Nevertheless, considering the role of DGKs in the coordination of synaptic environments for synaptic plasticity, it would be highly valuable to understand how DGK-dependent regulations of synaptic plasticity affect learning and memory at the behavior level.

All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.

This work was supported by the Korea Institute of Science and Technology Institutional Program (Project No. 2E26190) and the Institute for Basic Science (IBS-R002-D1).