Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP

Abstract

Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐1+/− mice, which are animal correlates of human PRG‐1+/mut carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases.

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior

“…Tomosyn2 controls acetyl choline release from cholinergic nerve terminals (Geerts et al., 2015) and acetylcholine (ACh) is known to induce persistent γ-oscillations in the hippocampus (Picciotto et al., 2012). LysoPLD/ATX encodes one of the major enzymes involved in synthesis of lysophospatidic acid (LPA), a molecule with a key signaling role controlling both excitatory and inhibitory synapse functions (García-Morales et al., 2015, Vogt et al., 2015). LPA has a critical role in the nervous system: knockout of LPA1 receptor causes anxiety (Santin et al., 2009), which also characterizes the Slm2 mouse, and LysoPLD/ATX is essential for brain development (Greenman et al., 2015).…”

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…Plasticity-related gene 1 (PRG-1) is a member of the integrin family, which acts as a co-factor with LPA in modulating glutamate neurotransmission. It has been shown that the post-synaptic deficiency of PGR-1 prohibits LPA from entering the post-synaptic membrane, thereby leading to the accumulation of LPA in the synaptic cleft (Vogt et al, 2016). Thus, an increased level of LPA in the synaptic gap has been shown to have two complementary mechanisms which result in increased glutamate concentration in the synaptic cleft.…”

PRG-1 Regulates Synaptic Plasticity via Intracellular PP2A/β1-Integrin Signaling

“…Bioactive lipid phosphates initiate receptor-directed signaling cascades and regulate fundamental cellular processes (Moolenaar et al, 2004). PRG-1, however, interacts with LPA in a manner different from classical LPPs (McDermott et al, 2006) by enabling transmembrane transport of LPA to intracellular compartments (Trimbuch et al, 2009;Vogt et al, 2016). PRG-1 is expressed at postsynaptic sites of principal neurons and acts in a non-cell-autonomous fashion by controlling LPA in the synaptic cleft, which in turn stimulates presynaptic LPA receptors resulting in an increased release probability of glutamate vesicles at excitatory synapses (Tokumitsu et al, 2010;Trimbuch et al, 2009;Vogt et al, 2016).…”

“…PRG-1, however, interacts with LPA in a manner different from classical LPPs (McDermott et al, 2006) by enabling transmembrane transport of LPA to intracellular compartments (Trimbuch et al, 2009;Vogt et al, 2016). PRG-1 is expressed at postsynaptic sites of principal neurons and acts in a non-cell-autonomous fashion by controlling LPA in the synaptic cleft, which in turn stimulates presynaptic LPA receptors resulting in an increased release probability of glutamate vesicles at excitatory synapses (Tokumitsu et al, 2010;Trimbuch et al, 2009;Vogt et al, 2016). Previous studies have shown that various members of the PRG family play a role in regulating structural plasticity, including filopodia formation, neurite extension, and brain reorganization after lesion (Brauer et al, 2003;Broggini et al, 2010;Coiro et al, 2014;Peeva et al, 2006;Savaskan et al, 2004;Sigal et al, 2007;Velmans et al, 2013).…”

“…Interestingly, unlike other members of the type 2 phosphatidic acid phosphatase (PAP2) superfamily, PRG-1 contains an additional C-terminal hydrophilic domain of around 400 amino acids (aa) (Brauer et al, 2003). This domain has been shown to exhibit interaction motifs important for intracellular signaling cascades (Tokumitsu et al, 2010;Vogt et al, 2016), indicating an additional cell-autonomous function of PRG-1. Since (1) PRG-1 in the mouse brain is localized to the PSD of glutamatergic neurons, (2) its expression starts at embryonic day 19 (E19), and (3) it reaches its highest abundance in the third week of life (Brauer et al, 2003), i.e., during synaptogenesis and spine maturation, we hypothesized that PRG-1 could be involved in mediating these processes in a cell-autonomous fashion via its intracellular C terminus.…”