{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have highlighted the critical importance of synaptic phospholipid signaling in maintaining proper neuronal excitability and behavior. For example, loss of function in plasticity‐related proteins—exemplified by findings on PRG‐1—demonstrates that when the regulation of lysophosphatidic acid (LPA) uptake is compromised, glutamatergic synapses become hyperexcitable. This disturbance in LPA metabolism disrupts the excitation/inhibition (E/I) balance and alters cortical network function, ultimately predisposing individuals to stress‐related psychiatric symptoms. Modulation of bioactive lipid signaling, such as through inhibition of autotaxin that synthesizes LPA, shows promise as a therapeutic strategy in alleviating these glutamate‐dependent dysfunctions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn parallel, phospholipid phosphatase related 4 (PLPPR4)—a neuron‐specific membrane protein localized at the postsynaptic density of glutamatergic synapses—has emerged as a key regulator of neuronal plasticity and neurodevelopment. Genetic disruption of PLPPR4, through heterozygous deletions, nonsense mutations, or splice variants, has been linked to neurodevelopmental disorders including intellectual disability and autism spectrum disorder. Studies using patient‐derived induced pluripotent stem cell neurons reveal that loss of PLPPR4 function causes significant impairments in neuronal morphology, such as reduced dendritic protrusion density, shorter neurites, and diminished axon length. These morphological deficits are associated with dysregulation of the mTOR signaling pathway—a pathway essential for axon maturation and synaptic function—underscoring the role of PLPPR4 in modulating neuronal development and synaptic plasticity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Johannes Vogt, Jenq-Wei Yang, Arian Mobascher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular cause and functional impact of altered synaptic lipid signaling due to a prg-1 gene SNP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Mol Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/emmm.201505677"}], "href": "https://doi.org/10.15252/emmm.201505677"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26671989"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26671989"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Huanzheng Li, Qian Zhang, Ru Wan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PLPPR4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mTOR signalling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.17899"}], "href": "https://doi.org/10.1111/jcmm.17899"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37550884"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37550884"}]}]}]}