TY  - GEN
KW  - HPA axis 
KW  -  TrkB 
KW  -  interneuron 
KW  -  CCK 
KW  -  conditional mutagenesis
TI  - Defining the role of TrkB signalling in CCK-expressing neurons
Y1  - 2011///
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/12937/
ID  - heidok12937
N2  - The neurotrophin receptor TrkB has been shown to regulate neuronal survival, migration, differentiation and innervation in the peripheral and central nervous system. In the mature nervous system, it can modulate synaptic plasticity and excitatory neuron-specific deletion of Trkb results in compromised learning ability and impaired long-term potentiation. TrkB is also expressed in interneurons and was reported to regulate interneuron differentiation, synapse assembly, maintenance and development of inhibitory networks. Given the heterogeneity of interneurons, cell-specific approaches are required to study the function of TrkB in different interneuronal subtypes. This study investigates the role of TrkB in a specific subset of interneurons that express cholecystokinin (CCK). Trkb was specifically deleted from CCK-neurons by crossing a transgenic BAC-Cre mouse line that expresses Cre under the CCK-promotor (BAC-CCK-Cre line) to a Trkb-floxed mouse line. CCK-Cre specific Trkb-knockout mice (TrkbCCK-KO mice) develop mature-onset central obesity and show hyperactivity of the HPA axis with peripheral signs of hypercortisolism. Analysis of food intake revealed that central obesity is not associated with hyperphagia but is a cause of hypercortisolism. Furthermore, we show that hypercortisolism-induced obesity is associated with increased leptin and insulin levels. Hyperactivity of the HPA axis in TrkbCCK-KO mice is associated with increased activity of the central HPA axis regulator, the paraventricular nucleus of the hypothalamus (PVN). PVN activity is strictly regulated by surrounding inhibitory interneurons and glucocorticoid feedback inhibition. We show that GABAergic interneurons in the vicinity of the PVN are recombined in the BAC-CCK-Cre line and colocalize with the glucocorticoid receptor GR. Furthermore, we present data indicating an impaired glucocorticoid feedback inhibition in TrkbCCK-KO mice. TrkB was previously shown to interact directly with the GR leading to enhanced phosphorylation of PLC-gamma1 by TrkB. Analysis of mice with a mutation in either the PLC or SHC adaptor site of TrkB reveals that the phenotype observed here is dependent on PLC-gamma1 signaling. Therefore we conclude that TrkB signaling in hypothalamic CCK-interneurons integrates glucocorticoid feedback inhibition and is required for inhibitory control of PVN activity. 
AV  - public
A1  - Geibel, Mirjam
ER  -