Adding a new piece to the perisynaptic puzzle: PLCβ1 is a component of the perisynaptic signaling machinery (PSM) (Commentary on Fukaya et al.)

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Synapses are at least 104 times more numerous than neurons. Yet, each synapse is a highly complex molecular machine, with proteomic analyzes estimating the number of different proteins found on the postsynaptic side alone to be in the range of ∼1000s. The postsynaptic density (PSD) is a specialized organelle with a precise organization and a sophisticated architecture; for example, ionotropic glutamate receptors (AMPA and NMDA receptors) responsible for translating anterograde chemical information into a postsynaptic electrical signal are concentrated with their auxiliary proteins at the center of the PSD. In contrast, type I metabotropic glutamate receptors (mGluR1 and mGluR5), which use anterograde signals to activate molecular signaling cascades, are found outside of the PSD in the so-called perisynaptic zone (Somogyi et al., 1998). Fukaya et al. (2008, in this issue) utilized state-of-the-art quantitative molecular neuroanatomy techniques to reveal that phospholipase C β1 (PLCβ1), a major enzyme downstream of type I mGluRs, is also positioned perisynaptically at glutamatergic synapses of telencephalic principal neurons. This finding indicates that PLCβ1 is a component of the perisynaptic signaling machinery (PSM).

PLCβ enzymes have long been considered to function as metabolic hubs, because they can be activated upstream by several Gq/11-coupled receptors, and because they can trigger multiple downstream signaling pathways by hydrolyzing the membrane component phosphatidylinositol-4,5-bisphosphate (PIP2) into the second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). However, the PLCβ family consists of four isoforms and previous work by Kano’s and Watanabe’s groups has revealed that three of these isoforms have strictly complementary localization and physiological functions in the brain (Kano et al., 1998). Surprisingly, these prior studies did not identify PLCβ isoforms in a major population of forebrain neurons, the so-called principal cells, constituting ∼90% of telencephalic neurons. Fukaya and colleagues now report results based on a new and highly sensitive antibody against the missing isoform, PLCβ1. They demonstrated that PLCβ1 is indeed expressed by principal neurons (e.g., cortical pyramidal cells and striatal medium spiny neurons), whereas PLCβ4 is found exclusively in GABAergic interneurons in these areas. Importantly, the authors validated their findings in PLCβ1-knockout animals in an exemplary way. Their detailed light and electron microscopic analysis uncovered that PLCβ1 is located in the somatodendritic domain of principal cells, but is apparently absent from their axons. However, this rule cannot be generalized to other brain regions because certain cerebellar interneurons do not exhibit such a selective distribution of PLCβ1. Furthermore, quantitative postembedding immunogold staining analysis revealed that the majority of PLCβ1 is localized perisynaptically around the edge of PSD. Moreover, confocal laser scanning microscopy demonstrated that in dendritic spines, PLCβ1 is co-localized with upstream type I mGluRs and a downstream lipase, the endocannabinoid-synthesizing diacylglycerol lipase-α.

This latter finding has important implications for research on epilepsy. In mice deletion of the PLCβ1 gene results in premature death due to severe generalized epileptic seizures (Kim et al., 1997), suggesting that this enzyme modulates glutamatergic transmission. In addition, the machinery for endocannabinoid-synthesis has been implicated in a negative feed-back loop protecting postsynaptic neurons against excessive activation of glutamatergic synapses (Katona & Freund, 2008). Thus, the work of Fukaya et al. (2008) may open important new avenues to study the role of PLCβ1 in neuronal excitability and neuroexcitotoxicity.

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