Astrocyte Gpc5 overexpression prevents hippocampal synaptic hyperexcitability in APP/PS1 mouse

Abstract

AbstractBackgroundAstrocytes are essential regulators of synaptic function throughout life. They regulate the formation, maturation and elimination of new synapses, as well as modulate synaptic transmission, and provide nutritional support to neurons. Our lab and others have shown that with healthy aging astrocytes change their properties altering the expression of genes important for synaptic maintenance in brain regions vulnerable to Alzheimer’s disease (AD). We now investigated whether astrocytes present the same age‐associated changes in mouse models of AD. We also assess whether these astrocyte changes are contributing to the synaptic dysfunction and cognitive alterations observed in AD mouse models.MethodWe use BacTRAP technology to isolate hippocampal astrocyte RNA from two different mouse models of Alzheimer’s disease: a model of Tau pathology (MAPTP301S) and amyloidosis (APPswe/PS1dE9). We analyze astrocyte transcriptome at 3 different timepoints: 4, 6 and 12 months, and in male and female mice independently. To assess the contribution of astrocyte alterations to synaptic dysfunction, we manipulate astrocyte gene expression using a viral approach in APP/PS1 mice, and characterized synaptic function using electrophysiology path‐clamp recordings, and spatial learning with Barnes maze test.ResultBoth APP/PS1 and MAPTP301S models showed an upregulation of genes involved in astrocyte reactivity and neuroinflammation and a downregulation of genes important for synaptic support. Among the genes that were downregulated was Glypican 5 (Gpc5), an astrocyte factor important for synaptic maturation and stabilization. Interestingly, Gpc5 downregulation has also been reported in several other human Alzheimer’s disease transcriptional studies. When we overexpress Gpc5 in astrocytes in APP/PS1 mice, we found that APP/PS1 mice injected with the control virus showed an increase postsynaptic frequency in CA1 pyramidal neurons, and this hyperexcitability was no present in APP/PS1 mice overexpressing Gpc5. In addition, preliminary cognitive results from the Barnes maze test suggest that astrocyte Gpc5 overexpression also improves spatial learning in APP/PS1 and WT mice.ConclusionThis data show that astrocyte Gpc5 downregulation might contribute to synaptic dysfunction in AD. Overexpressing Gpc5 in astrocytes prevents synaptic hyperexcitability in APP/PS1 mice. These results open exciting new venues for using astrocytic factors as novel targets in AD.