Enhanced BDNF and TrkB Activation Enhance GABA Neurotransmission in Cerebellum in Hyperammonemia

Autores de CIPF

• 

  Yaiza Arenas Ortiz

  Autor

• 

  Marta Llansola Gil

  Autor

• 

  Vicente Felipo Orts

  Autor

Participantes ajenos a CIPF

• Martinez-Garcia, M

Grupos de Investigación

• Laboratorio de Neurobiología

  

  Jefe/a de Grupo

  Vicente Felipo Orts

Abstract

Background: Hyperammonemia is a main contributor to minimal hepatic encephalopathy (MHE) in cirrhotic patients. Hyperammonemic rats reproduce the motor incoordination of MHE patients, which is due to enhanced GABAergic neurotransmission in the cerebellum as a consequence of neuroinflammation. In hyperammonemic rats, neuroinflammation increases BDNF by activating the TNFR1-S1PR2-CCR2 pathway. (1) Identify mechanisms enhancing GABAergic neurotransmission in hyperammonemia; (2) assess the role of enhanced activation of TrkB; and (3) assess the role of the TNFR1-S1PR2-CCR2-BDNF pathway. In the cerebellum of hyperammonemic rats, increased BDNF levels enhance TrkB activation in Purkinje neurons, leading to increased GAD65, GAD67 and GABA levels. Enhanced TrkB activation also increases the membrane expression of the gamma 2, alpha 2 and beta 3 subunits of GABA(A) receptors and of KCC2. Moreover, enhanced TrkB activation in activated astrocytes increases the membrane expression of GAT3 and NKCC1. These changes are reversed by blocking TrkB or the TNFR1-SP1PR2-CCL2-CCR2-BDNF-TrkB pathway. Hyperammonemia-induced neuroinflammation increases BDNF and TrkB activation, leading to increased synthesis and extracellular GABA, and the amount of GABA(A) receptors in the membrane and chloride gradient. These factors enhance GABAergic neurotransmission in the cerebellum. Blocking TrkB or the TNFR1-SP1PR2-CCL2-CCR2-BDNF-TrkB pathway would improve motor function in patients with hepatic encephalopathy and likely with other pathologies associated with neuroinflammation.

Keywords

• hyperammonemia; cerebellum; GABAergic neurotransmission; TrkB; BDNF; neuroinflammation; Purkinje neuron; GABA(A) receptors; motor incoordination; minimal hepatic encephalopathy