Requirements of BDNF and MMP9 for the neurotrophic effects of leptin in the developing hippocampus

Jose Luis Rodriguez Llamas

doi:10.7273/000007456

Neurotrophic factors direct the development of the nervous system, and impairments in their function lead to neurological disorders. Therefore, understanding how they regulate brain development is of paramount importance. Leptin is a hormone primarily released from the adipose tissue involved in the regulation of energy balance. However, leptin also exerts neurotrophic effects on the central nervous system. Leptin is also produced in the hippocampus, where it promotes spinogenesis, synaptic plasticity, and neurogenesis, while rodent models with altered leptin signaling exhibit impairments in these processes and defects in hippocampal-related functions, such as impaired learning and spatial memory. Notably, altered leptin signaling is also associated with mental and cognitive disorders in humans. These disorders are characterized by changes in dendritic spines, small dendritic protrusions that constitute the postsynaptic domain of excitatory glutamatergic synapses. Remarkably, our laboratory has shown that leptin increases the number of dendritic spines and the frequency of mini excitatory postsynaptic currents (mEPSCs) in developing hippocampal pyramidal neurons in vitro and in vivo, evidencing an increase in functional glutamatergic synapses. Since morphological changes in dendritic spines are considered the structural basis of learning and memory, leptin's role in spinogenesis may explain the defects observed in rodent models with impaired leptin signaling. Nonetheless, the molecular mechanisms underlying leptin neurotrophic effects are poorly understood. In the following chapters, I describe new signaling pathways through which leptin exerts its neurotrophic effects to regulate glutamatergic synaptogenesis in the developing hippocampus. In chapter one, I report the interaction of leptin signaling with brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates multiple processes in the hippocampus. I show that the BDNF signaling pathway is essential for leptin actions on synaptogenesis, as blocking it prevents leptin effects on dendritic spines in vitro and in vivo and leptin-induced increase in mEPSCs in vivo, highlighting the role that BDNF plays in leptin-induced increase in the number of functional glutamatergic synapses. Furthermore, I show a new mechanism by which leptin regulates BDNF in cultured hippocampal neurons: the direct stimulation of BDNF release. I describe that transient receptor potential channels type C (TrpC) are essential for leptin-induced BDNF release and that this process also requires the contribution of extracellular and intracellular Ca2+ sources. In chapter two, I describe my findings about the requirements of the protease matrix metalloproteinase 9 (MMP9) for the neurotrophic effects of leptin on synaptogenesis. I show that leptin regulates MMP9 at multiple levels, promoting Mmp9 expression and transport to the dendrites, as well as increasing MMP9 release and extracellular activity. Like BDNF, leptin also requires MMP9 activity to increase dendritic spines in vitro and in vivo and mEPSCs in vivo. Finally, leptin also requires the lysosome protease cathepsin B, a well-known activator of MMP9, as knocking down its expression prevents leptin effects on dendritic spines in hippocampal neurons. Together, these studies show the complexity of leptin signaling, highlighting how its interaction with other synaptic plasticity regulators directs glutamatergic synaptogenesis in the developing hippocampus. Thus, our findings advance our understanding of the molecular mechanisms through which leptin promotes spinogenesis and synaptic plasticity, contributing to the comprehension of the underlying mechanisms by which altered leptin signaling and leptin resistance lead to the development of neurological disorders.

Requirements of BDNF and MMP9 for the neurotrophic effects of leptin in the developing hippocampus

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