Amyotrophic lateral sclerosis (ALS) causes rapidly progressive paralysis and death within 5 years from diagnosis due to degeneration of the motor circuits. However, a significant population of ALS patients also shows cognitive impairments and progressive hippocampal pathology. Likewise, the mutant SOD1(G93A) mouse model of ALS (mSOD1), in addition to loss of spinal motor neurons, displays altered spatial behavior and hippocampal abnormalities including loss of parvalbumin-positive interneurons (PVi) and enhanced long-term potentiation (LTP). However, the cellular and molecular mechanisms underlying these morpho-functional features are not well understood. Since removal of TrkB.T1, a receptor isoform of the brain-derived neurotrophic factor, can partially rescue the phenotype of the mSOD1 mice, here we tested whether removal of TrkB.T1 can normalize the number of PVi and the LTP in this model. Stereological analysis of hippocampal PVi in control, TrkB.T1^−/−, mSOD1, and mSOD1 mice deficient for TrkB.T1 (mSOD1/T1^−/−) showed that deletion of TrkB.T1 restored the number of PVi to physiological level in the mSOD1 hippocampus. The rescue of PVi neuron number is paralleled by a normalization of high-frequency stimulation-induced LTP in the pre-symptomatic mSOD1/T1^−/− mice. Our experiments identified TrkB.T1 as a cellular player involved in the homeostasis of parvalbumin expressing interneurons and, in the context of murine ALS, show that TrkB.T1 is involved in the mechanism underlying structural and functional hippocampal degeneration. These findings have potential implications for hippocampal degeneration and cognitive impairments reported in ALS patients at early stages of the disease.

肌萎缩性侧索硬化症（ALS）在诊断后的5年内会由于运动回路的退化而导致快速进行性麻痹和死亡。但是，大量的ALS患者也显示出认知障碍和进行性海马病理。同样，ALS（mSOD1）的突变型SOD1（G93A）小鼠模型，除了丧失脊髓运动神经元外，还显示出空间行为和海马异常的改变，包括小白蛋白阳性中间神经元（PVi）的丧失和长期增强（LTP）的增强）。然而，这些形态功能特征背后的细胞和分子机制还没有被很好地理解。由于TrkB.T1（脑源性神经营养因子的受体同种型）的去除可以部分拯救mSOD1小鼠的表型，因此在此我们测试了TrkB是否去除。T1可以在此模型中归一化PVi和LTP的数量。对照TrkB.T1的海马PVi的体视学分析TrkB.T1（mSOD1 / T1 ^-/-）缺陷的^-/-，mSOD1和mSOD1小鼠显示TrkB.T1的缺失使mSOD1海马中的PVi数量恢复到生理水平。PVi神经元数目的挽救与有症状的mSOD1 / T1 ^-/-小鼠中高频刺激诱导的LTP正常化并行。我们的实验确定TrkB.T1是参与表达小白蛋白表达神经元稳态的细胞参与者，在鼠ALS的背景下，表明TrkB.T1参与了结构和功能性海马变性的机制。这些发现对疾病早期的ALS患者中报告的海马变性和认知障碍具有潜在的影响。