Professor Ian Forsythe

Tel: 0116 252 5580    Email: idf@le.ac.uk

Professor Ian ForsytheMolecular Neurophysiology at the Synaptic Interface

Laboratory Members: Emanuele Schiavon, Joshua Smalley, Beatrice Pigott, Jonathan Roberts, Sarah Lucas.

PhD Students: Deborah Linley.  I am co-supervising Julieta Campi and Marie Nugent.

Alumni: Postdocs: Sue Robinson, Matt Barker, Conny Kopp-Scheinpflug, Nadia Pilati, Joern Steinart, Tina Tong, Tanya Chernova, Rachael Hardman, Mike Postlethwaite, Sarah Griffn, Martine Hamann, Brian Billups, Euan Brown, Adrian Wong, Matt Cuttle, Helen Brew, Margaret Barnes-Davies.

Alumni: Postgrads: Jim Sinclair Adam Tozer, Martin Haustein, Jamie Johnston, Paul Dodson, Steve Owens, Amanda Smith, Joanne Doughty.

Collaborators: Blair Grubb, Margaret Barnes-Davies, Richard Evans, John Challiss, Martine Hamann, Martyn Mahaut-Smith, Rodrigo Quian Quiroga, Ezio Rosato, Bambos Kryiacou, Flav Giorgini (Leicester); Bruce Graham (Stirling), Matthias Hennig (Edinburgh), Osvaldo Utichel (Buenos Aries), Bruce Walmsley (Australia), Len Kaczmarek (USA).

Research Funding: Action on Hearing Loss, MRC, The Wellcome Trust, BBSRC, AgeUK, Rosetrees Trust.

Methods used: Electrophysiology, multi-electrode array, patch-recording, in vitro brain slice, calcium imaging, immunohistochemistry, quantitative PCR, microarray, confocal microscopy, auditory stimulation and response.

Summary: The writer and biochemist Issac Asimov, 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 and lay summary

Research Interests:

1The 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.

2Acoustic 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;

MNTB Calyx

 

Fig 1. Confocal image of red dextran-labelled axons and their giant synapses in the MNTB.

 

 

 

 

3. Synaptic Signalling – Transmission at the calyx of Held/MNTB synapse as shown above (Fig 1.) The calyx of Held is a giant synapse that 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.

Our research interests focus on understanding how ion channels and synaptic signalling contribute to neuronal function and dysfunction.  This involves exploration of presynaptic mechanisms and postsynaptic neuronal excitability.  We work predominately in the auditory brainstem because this region has a clear physiological function in processing sound information from both ears to produce information on the location of a sound source.  This allows us to interpret ion channel properties in terms of their function in a Physiological System.  This region also contains a unique giant synapse called the Calyx of Held from which we may ask fundamental questions about the control of synaptic transmission, the mechanism of auditory processin gand the strategies which may give insight into auditory and broader nervous system disease.

Selected Publications:

Jalabi W, Kopp-Scheinpflug C, Allen PD, Schiavon E, DiGiacomo RR, Forsythe ID, Maricich SM (2013). Sound localization ability and glycinergic innervation of the superior olivary complex persist after genetic deletion of the medial nucleus of the trapezoid body. J Neurosci. 33: 15044-9.

Tong H, Kopp-Scheinpflug C, Pilati N, Robinson SW, Sinclair JL, Steinert JR, Barnes-Davies M, Allfree R, Grubb BD, Young SM Jr, Forsythe ID (2013). Protection from noise-induced hearing loss by Kv2.2 potassium currents in the central medial olivocochlear system. J Neurosci. 33: 9113-21.

Inchauspe CG, Urbano FJ, Di Guilmi MN, Ferrari MD, van den Maagdenberg AM, Forsythe ID, Uchitel OD (2012). Presynaptic CaV2.1 calcium channels carrying familial hemiplegic migraine mutation R192Q allow faster recovery from synaptic depression in mouse calyx of Held. J Neurophysiol. 108: 2967-76.

Tong H, Kopp-Scheinpflug C, Pilati N, Robinson SW, Sinclair JL, Steinert JR, Barnes-Davies M, Allfree R, Grubb BD, Young SM Jr, Forsythe ID (2013). Protection from noise-induced hearing loss by Kv2.2 potassium currents in the central medial olivocochlear system. J Neurosci. 33: 9113-21.

Steinert JR, Campesan S, Richards P, Kyriacou CP, Forsythe ID, Giorgini F. (2012) Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington's disease. Hum Mol Genet. 21:2912-22.

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, Ca2+ 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.

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Department of Neuroscience, Psychology and Behaviour
University of Leicester
University Road
Leicester
LE1 7RH

T: +44 (0)116 252 2922