Altered synaptic phospholipid signaling in PRG-1 deficient mice induces exploratory behavior and motor hyperactivity resembling psychiatric disorders

Abstract

Plasticity related gene 1 (PRG-1) is a neuron specific membrane protein located at the postsynaptic density of glutamatergic synapses. PRG-1 modulates signaling pathways of phosphorylated lipid substrates such as lysophosphatidic acid (LPA). Deletion of PRG-1 increases presynaptic glutamate release probability leading to neuronal over-excitation. However, due to its cortical expression, PRG-1 deficiency leading to increased glutamatergic transmission is supposed to also affect motor pathways. We therefore analyzed the effects of PRG-1 function on exploratory and motor behavior using homozygous PRG-1 knockout (PRG-1−/−) mice and PRG-1/LPA2–receptor double knockout (PRG-1−/−/LPA2−/−) mice in two open field settings of different size and assessing motor behavior in the Rota Rod test. PRG-1−/− mice displayed significantly longer path lengths and higher running speed in both open field conditions. In addition, PRG-1−/− mice spent significantly longer time in the larger open field and displayed rearing and self-grooming behavior. Furthermore PRG-1−/− mice displayed stereotypical behavior resembling phenotypes of psychiatric disorders in the smaller sized open field arena. Altogether, this behavior is similar to the stereotypical behavior observed in animal models for psychiatric disease of autistic spectrum disorders which reflects a disrupted balance between glutamatergic and GABAergic synapses. These differences indicate an altered excitation/inhibition balance in neuronal circuits in PRG-1−/− mice as recently shown in the somatosensory cortex [38]. In contrast, PRG-1−/−/LPA2−/− did not show significant changes in behavior in the open field suggesting that these specific alterations were abolished when the LPA2-receptor was lacking. Our findings indicate that PRG-1 deficiency led to over-excitability caused by an altered LPA/LPA2-R signaling inducing a behavioral phenotype typically observed in animal models for psychiatric disorders.