Lrp4 in astrocytes modulates glutamatergic transmission

Abstract

Neurotransmission requires precise control of neurotransmitter release from axon terminals. This process is regulated by glial cells; however, underlying mechanisms are not fully understood. Here we report that glutamate release in the brain is impaired in mice lacking low density lipoprotein receptor-related protein 4 (Lrp4), a protein critical for neuromuscular junction formation. Electrophysiological studies indicate compromised release probability in astrocyte-specific Lrp4 knockout mice. Lrp4 mutant astrocytes suppress glutamate transmission by enhancing the release of ATP, whose levels are elevated in the hippocampus of Lrp4 mutant mice. Consequently, the mutant mice are impaired in locomotor activity and spatial memory and are resistant to seizure induction. These impairments could be ameliorated by adenosine A1 receptor antagonist. The results reveal a critical role of Lrp4, in response to agrin, in modulating astrocytic ATP release and synaptic transmission. Our study provides insight into the interaction between neurons and astrocytes for synaptic homeostasis and/or plasticity.

Neuronal LRP4 regulates synapse formation in the developing CNS

“…Studies in LRP4-deficient mice rescued from perinatal death by re-expression of LRP4 in the neuromuscular system, as well as mice with a selective loss of the intracellular and the transmembrane domains showed a significantly decreased density of dendritic spines in the CA3-hippocampal region, but had no gross anatomical abnormalities in the prenatal and adult hippocampus, cortex and cerebellum (Pohlkamp et al, 2015;Gomez et al, 2014). In addition, Lrp4 mRNA is present in the neocortex, hippocampus, cerebellum and olfactory bulb (Sun et al, 2016;Lein et al, 2007;Tian et al, 2006). A recent study (Sun et al, 2016) reported that in adult mice β-galactosidase expression driven by the endogenous Lrp4 promoter is mostly detectable in astrocytes, which is in concordance with our data showing that LRP4 levels, detected by western blotting, are higher in astrocytes than in neurons (Fig.…”

“…S1). The specificity of the LRP4 antibodies used for immunocytochemistry was confirmed by western blotting, where a single band with an apparent molecular mass of 250 kDa was detected in cultured astrocytes, as previously described (Sun et al, 2016), as well as extracts from cultured embryonic neurons (Fig. 1D).…”

“…In addition to the PNS, LRP4 plays crucial roles in the adult CNS, including maintenance of excitatory synaptic transmission, hippocampal synaptic plasticity, fear conditioning, associative and spatial learning, and long-term potentiation (Gomez et al, 2014;Pohlkamp et al, 2015;Sun et al, 2016). Accordingly, Lrp4 mRNA is present in the neocortex, hippocampus, cerebellum and olfactory bulb (Lein et al, 2007;Sun et al, 2016;Tian et al, 2006).…”

“…Accordingly, Lrp4 mRNA is present in the neocortex, hippocampus, cerebellum and olfactory bulb (Lein et al, 2007;Sun et al, 2016;Tian et al, 2006). Moreover, LRP4 protein has been detected in postsynaptic membrane fractions purified from adult rat forebrain where it interacts with the postsynaptic scaffold protein PSD95 (also known as DLG4) (Gomez et al, 2014;Tian et al, 2006).…”

“…Moreover, LRP4 protein has been detected in postsynaptic membrane fractions purified from adult rat forebrain where it interacts with the postsynaptic scaffold protein PSD95 (also known as DLG4) (Gomez et al, 2014;Tian et al, 2006). Recently, astrocyteexpressed LRP4 activated by agrin has been shown to modulate glutamatergic synaptic transmission by regulating the release of ATP from astrocytes (Sun et al, 2016). Although these data show a requirement of astroglial LRP4 for normal function of the adult brain, it is still unknown whether LRP4 regulates synaptogenesis in the developing CNS in a similar way as at the NMJ.…”