Lípidos bioactivos como reguladores de la eficacia sináptica y excitabilidad intrínseca de motoneuronas in vitro

  1. Victoria García Morales
Supervised by:
  1. Bernardo Moreno López Director

Defence university: Universidad de Cádiz

Fecha de defensa: 09 June 2017

  1. Federico Portillo Pacheco Chair
  2. Cristina Alba Delgado Secretary
  3. José Luís Nieto González Committee member
  1. Biomedicina, Biotecnología y Salud Pública

Type: Thesis

Teseo: 478353 DIALNET


Synaptic transmission is a dynamic process that is key for the regulation of neuronal excitability and information processing in the brain. Short-term modifications of synaptic strength are essential to ensure the synaptic excitation and inhibition balance, a fundamental requirement in the sensory, cognitive and motor functions of living organisms. There are several molecular mechanisms involved in synaptic plasticity processes responsible for maintaining the synaptic strength at physiological states. Alteration of the size of the readily release readily releasable pool (RRP) of neurotransmitters vesicles at presynaptic terminal or regulation of intrinsic excitability in the postsynaptic component, are mechanisms mainly underlying short-term synaptic plasticity. In this sense, some substances can act by modifying the synaptic strength at several pathophysiological conditions. Bioactive lipids are a group of lipids of different nature, which play a pivotal role in cell signalling, acting as neuromodulators in the nervous system. Bioactive lipids concentration and function are disturbed in the central nervous system at different neurological disorders, such as anxiety, learning, behavioural or psychiatric disorders. However, the role of these neuromodulators in the control of motoneuron (MN) physiology is poorly known. In this sense, cannabinoids (CBs) and lysophosphatidic acid (LPA) could be promising candidates to regulate motor commands by regulating MN function. The endocannabinoid system (eCB) is a neuromodulator system with an important role in neuronal function and behaviour. Generally, presynaptic CB1 receptor activation induces short-term synaptic depression by a molecular mechanism poorly understood. In this work, exogenous application of CBs induced a reduction in the size of the RRP in excitatory terminal on hypoglossal MNs (HMNs) by a CB1-dependent manner. This was accompanied by short-term depression of excitatory synaptic strength. Membrane depolarization of the postsynaptic neuron induced short-term depression at excitatory synapses in a CB1-dependent manner indicating that CBs act as retrograde messengers in this process. These outcomes suggest a the coupling of CBs synthesis to neuron activity. On the other hand, application of LPA induced short-term depression in excitatory and inhibitory synapses on HMNs. At the excitatory ones, LPA decreased the size of the RRP in a cytoskeleton actin-myosin-dependent mechanism. At inhibitory synapses, LPA treatment favoured dephosphorylation and internalization of the GABAA γ2 subunit. In addition, activation of LPA receptors increased intrinsic membrane excitability of HMNs by inhibition of TASK-1 background K+ channels. In certain pathological conditions such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington or Parkinson's, exist an imbalance in LPA concentrations and its receptors in the brain. So that could be interesting to investigate the role of signalling mechanism imbalance at several neurologic conditions. Altogether, these results suggest a modulator role of these bioactive lipids in the control of motor commands and brain function at physiological and pathological states.