Tel: 0116 252 5088    Email: idf@le.ac.uk

Molecular Neurophysiology at the Synaptic Interface

Laboratory Members:  Conny Kopp-Scheinpflug, Nadia Pilati, Emanuele Schiavon. PhD Students: Adam Tozer, Jim Sinclair; (Co-supervisor): Marie Nugent, Julieta Campi.
Collaborators: Joern Steinart, Blair Grubb, Margaret Barnes-Davies, Richard Evans, Martine Hamann, Martyn Mahaut-Smith, Rodrigo Quian Quiroga, Ezio Rosato.
Research Funding: The Wellcome Trust, Action on Hearing Loss, Deafness Research UK, MRC.
Methods used: Electrophysiology, patch-clamp, calcium imaging, fluorescent immunohistochemistry, quantitative PCR, confocal microscopy, auditory stimulation and response.

Summary: The astronomer and writer Carl Sagan, suggested that “the brain is the most complex matter in the known universe”. Our laboratory studies brain function with a particular emphasis on the ‘synapse’ – the site at which information is transmitted between brain cells.  Our research focuses on understanding how the brain achieves a particular function, such as hearing or listening and understanding diseases such as deafness, tinnitus, epilepsy, neurodegeneration and dementia.

Further information

Research Interests:

Confocal image of red dextran-labelled axons and their giant synapses in the MNTB.

1. The ionic and molecular mechanism of auditory processing. Each of the nuclei in the superior olivary complex contribute to processing the binaural information. By studying the ionic conductances underlying their responses and action potential firing, we can elucidate the physiological roles of specific ion channels. Recently we discovered that the offset firing response in the superior olivary complex requires 3 complementary adaptations: a large Chloride gradient is generated by the KCl co-transporter KCC2. A glycinergic IPSP then activates the ‘hyperpolarization activated non-specific cation channels’, IH. This in turn triggers rebound firing of action potentials at the end of a sound (Kopp-Scheinpflug et al., 2011). This forms a highly sensitive gap-detection mechanism required for auditory communication and language.

2. Acoustic Trauma – Disease mechanisms in the central auditory pathway. It is well established that exposure to loud sounds can cause deafness due to damage of the hair cells in the cochlea. However such sounds also cause extreme activation of the auditory neurons and this can cause changes to the central auditory pathway which may mitigate or exacerbate the peripheral injury. We have several projects focussed on understanding central contributions to auditory disease:

a) the medial olivocochlear system in age-related deafness and the role of Kv2.2 potassium channels;

 b) understanding the mechanisms of toxicity and neurodegeneration caused by bilirubin in Jaundice;

 c) characterising the damage caused in central synaptic pathways on exposure to loud sounds;

3. Synaptic Signalling – Transmission at the calyx of Held/MNTB synapse. The calyx of Held allows direct patch recording from both the presynaptic terminal and its target – the MNTB principal neuron. This glutamatergic synapse provides a unique opportunity to study presynaptic mechanisms of exocytosis and the postsynaptic excitatory synaptic currents. A particular interest is in the presynaptic modulatory mechanisms controlling release probability and vesicle recycling. Recent studies have characterised the development of NMDAR using electrophysiological and PCR methods. 

4. Potassium channels and intrinsic excitability. We have a long term interest in the physiological role of different voltage-gated potassium channels and in addressing the question of why are there so many K_⁺ channel subunit genes for ‘delayed rectifiers’? We have focussed on the voltage-gated potassium channel families Kv1, Kv2, Kv3 and Kv4. Subunits from each of these families are expressed in the MNTB neuron and in the majority of neurones across the brain. Our most recent work has shown that nitric oxide evoked by synaptic stimulation suppresses Kv3 channels and facilitates Kv2, thereby switching the basis of action potential repolarisation in the MNTB and CA3 region of the hippocampus (Steinert et al., 2011). These results show that target neuron excitability is under the control of the incoming synaptic activity.

Recent Publications:

Kopp-Scheinpflug C, Tozer AJ, Robinson SW, Tempel BL, Hennig MH, Forsythe ID. (2011). The sound of silence: ionic mechanisms encoding sound termination. Neuron 71: 911-25. PubMed PMID: 21903083.

Lippi G, Steinert JR, Marczylo EL, D'Oro S, Fiore R, Forsythe ID, Schratt G, Zoli M, Nicotera P, Young KW. (2011) Targeting of the Arpc3 actin nucleation factor by miR-29a/b regulates dendritic spine morphology. J Cell Biol. 194: 889-904. PubMed PMID: 21930776.

Steinert JR, Robinson SW, Tong H, Haustein MD, Kopp-Scheinpflug C, Forsythe ID.(2011) Nitric oxide is an activity-dependent regulator of target neuron intrinsic excitability. Neuron 71: 291-305. PubMed PMID: 21791288.
Kopp-Scheinpflug C, Steinert JR, Forsythe ID. (2011) Modulation and control of synaptic transmission across the MNTB. Hear Res; 279: 22-31. PubMed PMID: 21397677.

Haustein MD, Read DJ, Steinert JR, Pilati N, Dinsdale D, Forsythe ID. (2010) Acute hyperbilirubinaemia induces presynaptic neurodegeneration at a central glutamatergic synapse. J Physiol. 588: 4683-93. PubMed PMID: 20937712.

Steinert JR, Chernova T, Forsythe ID. (2010) Nitric oxide signaling in brain function, dysfunction, and dementia. Neuroscientist 16:435-52. PubMed PMID: 20817920.

Johnston J, Forsythe ID, Kopp-Scheinpflug C. (2010) Going native: voltage-gated potassium channels controlling neuronal excitability. J Physiol. 588: 3187-200. PubMed PMID: 20519310.

McCloskey C, Jones S, Amisten S, Snowden RT, Kaczmarek LK, Erlinge D, Goodall  AH, Forsythe ID, Mahaut-Smith MP. (2010) Kv1.3 is the exclusive voltage-gated K_⁺ channel of platelets and megakaryocytes: roles in membrane potential, Ca^₂₊ signalling and platelet count. J Physiol. 588: 1399-406. PubMed PMID: 20308249.

Tong H, Steinert JR, Robinson SW, Chernova T, Read DJ, Oliver DL, Forsythe ID. (2010) Regulation of Kv channel expression and neuronal excitability in rat medial nucleus of the trapezoid body maintained in organotypic culture. J Physiol. 588: 1451-68. PubMed PMID: 20211981.

Steinert JR, Kopp-Scheinpflug C, Baker C, Challiss RA, Mistry R, Haustein MD, Griffin SJ, Tong H, Graham BP, Forsythe ID. (2008) Nitric oxide is a volume transmitter regulating postsynaptic excitability at a glutamatergic synapse. Neuron 60: 642-56. PubMed PMID: 19038221.