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Updated: Sep 12, 2025
Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
Targeting S1PR1 with W146 Ameliorates autism-associated cognitive deficits by restoring neurovascular integrity via
Gang Zhao1, Xian Tian2, Kangwei Peng1
1Department of Child Health Care, Maternity and Child Healthcare Hospital of Nanshan District, 1 Wanxia Road, Nanshan District, Shenzhen 518067, China.
Objective:
We investigated the role of sphingosine-1-phosphate receptor 1 (S1PR1) in blood-brain barrier (BBB) function and associated behavioral abnormalities using the BTBR T + tf/J (BTBR) mouse model of autism.
Methods:
Male C57BL/6 J (C57) and BTBR mice (4-week-old, n = 16/group) were assigned to three groups: C57 + Veh, BTBR+Veh, and BTBR+W146. The BTBR+W146 group received daily intraperitoneal injections of W146 (1 mg/kg) for 21 days, while control groups received equivalent volumes of vehicle (DMSO+0.9 % saline). Learning and memory were assessed using the Morris water maze. S1PR1 expression was determined via RT-PCR and Western blot analysis. Hippocampal neuronal morphology was examined by Nissl staining, while microvascular endothelial markers (CD31) and apoptotic pathway proteins (p-ERK, Caspase-3) were assessed by immunohistochemistry and Western blot.
Results:
BTBR mice showed significantly higher hippocampal S1P and S1PR1 than C57 controls (P < 0.01). W146 treatment reduced escape latency and increased platform crossings in the Morris water maze (P < 0.05). Treatment with W146 also increased phospho-Ca2+/calmodulin-dependent protein kinase II (p-CaMKII), and phospho-cAMP-response element binding protein (p-CREB) expression in the hippocampus. Histologically, W146 restored neuronal density in the hippocampal CA1 region and preserved microvascular integrity, as shown by increased CD31 expression (P < 0.05). The observed neuroprotective effect was linked to significant decreases in the expression of phosphorylated ERK (P < 0.05) and Caspase-3 (P < 0.05).
Conclusion:
Elevated S1P/S1PR1 signaling in BTBR mice is associated with hippocampal neurovascular dysfunction. Treatment with the S1PR1 antagonist W146 improves learning and memory deficits, coinciding with reduced ERK/Caspase-3-mediated apoptotic signaling and preserved CA1 neuronal integrity. These findings highlight S1PR1 as a potential therapeutic target for autism-related cognitive impairments.
