Deletion of the BDNF receptor TrkB.T1 rescues hippocampal parvalbumin positive interneurons in a mouse model of Amyotrophic Lateral Sclerosis

In addition to motoneurons degeneration, Amyotrophic Lateral Sclerosis (ALS) patients have defects in brain regions primarily associated with cognitive functions, such as the hippocampus. These defects have also been confirmed in animal models of ALS. The report that transgenic mice expressing a mutant form of the human superoxide dismutase-1 (hSOD1) with a Gly93 → Ala substitution (G93A-hSOD1), causing familial ALS, have degeneration of a subsets of spinal interneurons (Mol Neurobiol. 2012, 45: 30-42) prompted us to investigate whether this phenotype extends to other CNS interneuron populations. The calcium-binding protein parvalbumin positive interneurons (PVi), constitute the largest class of hippocampal interneurons and play essential roles in hippocampus development and plasticity. Interestingly, we found that PVi are reduced in the hippocampus of presymptomatic G93A-hSOD1 mice compared to controls. Therefore, we decided to use the hippocampal PVi as a model system to identify pathways that may affect the survival of this neuronal population in neurodegenerative conditions. Recently we have shown that deletion of the BDNF receptor TrkB.T1 lacking the intracellular tyrosine kinase domain delays the onset of motoneuron degeneration in the G93A-hSOD1 mice (PLoS One. 2012, 7:e39946). Thus, we investigated hippocampal PVi in G93A-hSOD1/TrkB.T1 deficient mice, G93A-hSOD1 animals at the presymptomatic state and wild type mice as controls. Eight-week-old brains were processed to visualize PVi. After image acquisition, hippocampal slices stained for PV were analyzed with ImageJ. Surprisingly, we found that the number of hippocampal PVi was comparable between wild type and G93A-hSOD1/TrkB.T1-/-. Statistical analysis by ANOVA performed on raw data revealed highly significant differences among the three genotypes [F(2,137)=9.077, p=0.0002]. Post-hoc tests showed that G93A-hSOD1 mice had significantly less PVi (79.05±0.56) compared to wild type (93.84±0.93) and to G93A-hSOD1/TrkB.T1-/- mice (93.10±0.54). These data suggest that BDNF/TrkB.T1 signaling affects not only motoneurons but also hippocampal PVi survival. Moreover, they unveil a new function for TrkB.T1 in a cell population essential for normal hippocampal function and suggest the relevance of targeting this pathway in neurodegenerative conditions.