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Title: Investigating the modulation of neonatal rat facial motoneurone excitability by monoamine neurotransmitters : postsynaptic mechanisms and presynaptic modulation of glutamate release
Author: Perkins, Emma M.
ISNI:       0000 0004 2726 0101
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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The activity patterns of 5-HT-releasing neurons can be positively correlated with behavioural state and motor function and the central 5-HT system modulates motor activity at the cellular level. The rat facial motor nuclei are densely innervated by 5- HT releasing afferents and 5-HT-mediated modulation of ion channels on the soma and dendrites can markedly influence the excitability of facial motoneurones and their integration of excitatory postsynaptic potentials (EPSPs). 5-HT facilitates facial motoneuron excitation by inhibiting a ‘leak’ potassium (K+) conductance (gK+ Leak) and enhancing the hyperpolarisation-activated cation current, Ih. These actions of 5- HT have been confirmed using whole-cell voltage-clamp recordings from visually identified facial motoneurones in an acute brainstem slice preparation. Pharmacological approaches have been used to identify the receptors which mediate the actions of 5-HT in facial motoneurones. The inhibition of gK+ Leak by 5-HT can be blocked by the 5-HT2A receptor antagonist, R96544 (0.3 – 1μM) and the enhancement of Ih by 5-HT is sensitive to the 5-HT7 receptor antagonist, SB269970 (0.3 – 10 μM). Noradrenaline was also found to inhibit gK+ Leak, via activation of a1 adrenoceptors, and the molecular identity of the amine-sensitive ‘leak’ K+ channels has been investigated. TASK-1 and TASK-3 are pH-sensitive two-pore domain K+ channels that can be modulated by amines and provide ‘leak’ K+ conductances in several central neurones. The mRNAs for these channels have been reported to be present in the rat facial motor nucleus. The gK+ Leak in facial motoneurones is sensitive to changes in external pH and has a pK of ~7.1, which is intermediate between the v values for homomeric TASK-1 and TASK-3 channels (7.5 and 6.8 respectively). The TASK-1 selective inhibitor anandamide (10 μM), its stable analogue methanandamide (10 μM), the TASK-3 selective inhibitor ruthenium red (10 μM) and Zn2+ (100-300 μM) all failed to alter the actions of noradrenaline or changing external pH. These findings argue against principal contributions to gKLeak by homomeric TASK-1 or TASK-3 channels. Isoflurane, a volatile anaesthetic that enhances heteromeric TASK-1 / TASK-3 currents, potentiated gKLeak supporting a predominant role for heterodimeric TASK-1 / TASK-3 channels in the gKLeak in facial motoneurones. Evoked fast excitatory synaptic transmission in the facial motor nucleus has been characterised and NMDA and non-NMDA receptor-mediated components of this synaptic transmission have been identified. Through a combination of analysis of the paired pulse ratio, rate of failure to generate a response and the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) this study provides evidence to suggest that glutamate release from pre-synaptic terminals in the facial motor nucleus is depressed by 5-HT. This action of 5-HT is mediated by activation of presynaptic 5-HT1B receptors as this effect is mimicked by the 5-HT1B receptor agonist, CP93129 (10 μM) and can be blocked by the 5-HT1B receptor antagonist, isamoltane (1 μM). These studies indicate that the modulation of synaptic integration in the facial motor nucleus involves activation of distinct pre- and post-synaptic 5-HT receptor subtypes. These findings not only increase our understanding of the cellular mechanisms for vi the 5-HT modulation of motor activity but may also be relevant to the role of 5-HT in the control of other central neurones.
Supervisor: Larkman, Phillip. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biomedical Science ; Neuroscience