Brain‐Derived Neurotrophic Factor ( BDNF ), Estrogen Receptors, and Mossy Cells

Dentate gyrus (DG) function depends on the neurotrophin brain-derived neurotrophic factor (BDNF) which shows robust synthesis in the principal cells, the granule cells (GCs). However, BDNF protein is present in the inner molecular layer (IML), where most afferents to GCs are from hilar mossy cells (MCs). Therefore, we asked whether MCs express BDNF mRNA and protein. Using adult mice, we found that MC BDNF mRNA and protein were expressed in the majority of MC somata and few other hilar neurons. Interestingly, IML BDNF was significantly greater in the ventral compared to dorsal DG. Additionally, dorsal IML BDNF was significantly higher in females on proestrous morning, when serum levels of estrogen peak, relative to metestrous morning, when estrogen is lower. Consistent with this observation, ventral MC somata, which project to the dorsal IML, showed more BDNF mRNA on proestrous morning than metestrous morning. Next, we asked if strong IML BDNF protein expression on proestrous morning was due to estrogen action at estrogen receptors (ERs) because estrogen binding to ERs can increase BDNF synthesis. We found that MCs have high expression of all ERs: ERα, ERβ and GPER1 in both sexes. When sexes were pooled, the percent of MCs labeled by ERβ and GPER1 exceeded the percent of MCs expressing ERα. When proestrous females were examined, GPER1-labeled hilar cells were greater than hilar cells labeled by ERα. The results demonstrate robust MC somatic expression of BDNF, relatively high ventral IML expression of BDNF, and estrous cycle dependence. The results also highlight robust MC ER expression, especially ERβ and GPER1, making the hilus a previously underestimated site of estrogen and BDNF action. HIGHLIGHTS BDNF mRNA and protein are expressed in most MCs and their axons in both sexes. Ventral MC axons in the distal inner molecular layer (IML) exhibit more BDNF protein than dorsal MC axons. Ventral MCs show relatively strong BDNF mRNA on proestrous morning compared to metestrous females. MCs express all 3 estrogen receptors (ERα, ERβ, GPER1) in both sexes, allowing estrogen to influence BDNF by MC ERs. GRAPHICAL ABSTRACT Top: A circuit diagram of the hippocampus shows cell layers in grey and the principal cell types (dentate gyrus granule cells, CA3 pyramidal cells, CA1 pyramidal cells). In the past. BDNF protein was considered to be produced mainly in granule cells and transported to their axons. Bottom: The implications of the present study are illustrated schematically. For example, hilar mossy cells (MCs) express BDNF mRNA and protein, and express all estrogen receptors (ERs): ERα, ERβ, GPER1. Therefore, MC ERs have the potential to play important roles in BDNF and estrogen action in the dentate gyrus.