Professor Ian Forsythe

Professor Ian Forsythe

Contact details

Tel: 0116 252 5580

Email: idf@le.ac.uk

Research

Molecular Neurophysiology at the Synaptic Interface

Laboratory Members:
Lab. Manager: Ms Michelle Hammett
Postdoctoral staff: Dr Sarah Lucas, Dr Emanuele Schiavon.
Postgraduate Students: Amy Richardson (BBSRC, CASE), Sherylanne Newton (Leicester), Deborah Linley (Action on Hearing Loss).

Visitors:
Leander Mrowka (Erasmus Exchange, Munich Germany)
Dan Cooper (MIBTP Mini-project, Warwick)

Alumni: Postdocs: Dr Beatrice Pigott, Dr Joshua Smalley, Dr Jonathan Roberts, Dr Conny Kopp-Scheinpflug, Sue Robinson, Dr Nadia Pilati, Dr Joern Steinert, Dr Tina Tong, Dr Tanya Chernova, Dr Rachael Hardman, Matt Barker, Dr Mike Postlethwaite, Dr Sarah Griffin, Dr Martine Hamann, Dr Brian Billups, Dr Euan Brown, Dr Adrian Wong, Dr Matt Cuttle, Dr Helen Brew, Dr Margaret Barnes-Davies.

Alumni: Postgrads: Dr Julieta Campi (2016), Dr Marie Nugent (2015), Dr Jim Sinclair (2014), Dr Adam Tozer (2013), Dr Martin Haustein (2011), Dr Jamie Johnston (2008), Dr Paul Dodson (2003), Dr Steve Owens (2003), Dr Amanda Smith (1998), Dr Joanne Doughty (1996).

Intercalated BSc Medical Students: Georgina Yan, Michael Leung, Haresh Selvaskandan, Rebecca Allfree, Jessica Sterenborg, Craig Sheridan, Fatima Osmani.

Collaborators: Rodrigo Quian Quiroga (CSN), Conny Kopp-Scheinpflug (Munich, Germany), Richard Evans (MCB), Bruce Graham (Stirling), Matthias Hennig (Edinburgh), Claire Gibson (NPB) Vincenzo Marra (NPB), Osvaldo Uchitel (Buenos Aries).

Research Funding: Action on Hearing Loss, EU - Horzion2020, MRC, The Wellcome Trust, BBSRC, Age UK, Rosetrees Trust.

Methods used: in vitro brain slice (brainstem, hippocampus, neocortex), multi-electrode array, patch-recording, voltage-clamp, calcium imaging, immunohistochemistry, confocal microscopy, quantitative rtPCR, RNA sequencing, western blot, auditory stimulation and auditory brainstem response, gene editing.

Summary: We are exploring how the brain works and how this causes or contributes to diseases when things go wrong. Our focus is on hearing, and we are interested in how information about sound is used by the brain; for example, to localize where a sound is coming from, or to listen to one voice in a crowded room. We are also interested in hearing-loss and deafness. We study how exposure to loud sounds damage the ear and the brain, causing tinnitus. There are many commonalities in the way different parts of the brain work, so that our discoveries about hearing also apply more widely, informing us of general rules governing brain function. For example, in epilepsy, stroke, ageing, neurodegeneration and dementia.

An image of the human brain, compared to the size of a mouse brain.
image1_The-human-brain.gif

Details of Research Interests:

1. Auditory processing. Each of the nuclei in the auditory brainstem contribute to processing information received from both ears (binaural). We use voltage-clamp to measure the synaptic and voltage-gated currents in identified neurons of each nucleus. By studying how synaptic currents integrate with the intrinsic currents to generate action potential firing, we can elucidate physiological mechanisms of auditory processing. For example, the ability to detect very short gaps in sound requires precise offset firing in the superior paraolivary nucleus (SPN). This offset firing requires three complementary processes: 1. A large chloride ion gradient is generated by the outwardly directed chloride pump or co-transporter KCC2. 2. A large glycinergic synaptic response (IPSP) then activates the ‘hyperpolarization-activated non-specific cation channels’, IH. 3. This suppresses activity during the sound, but causes rebound firing of action potentials at the end of a sound (Kopp-Scheinpflug et al., 2011) and so signals the ‘silence’ or end of a sound to higher levels of the brain. This enables gap-detection which is essential for vocal communication and language.

 

image2-The-Auditory-Brainstem-diagram.gif

 

The auditory brainstem receives information from both ears and computes the location of a sound – this is essential to escape from predators or to locate prey. Three of the key nuclei are labelled: LSO – lateral superior olive; SPN – superior paraolivary nucleus; MNTB – medial nucleus of the trapezoid body.

Background - the Brainstem Auditory Pathway

Sound is detected by the inner hair cells in the cochlea, which excite the spiral ganglion cell processes so that bursts of action potentials pass into the brain along the 8th Nerve and project into the Cochlear Nucleus. Bushy cells of the anterior Ventral Cochlear Nucleus (aVCN) give a large projection which crosses the midline and forms the giant synapse or Calyx of Held in the contralateral Medial Nucleus of the Trapezoid Body (MNTB) which is mediated by the neurotransmitter glutamate. So what does the calyx of Held synapse with the MNTB do? It provides an inhibitory glycinergic projection to three key nuclei in the Superior Olivary Complex (SOC): The Medial Superior Olive (MSO); which computes interaural timing differences (ITD). The Lateral Superior Olive (LSO); which integrates an ipsilateral excitatory input with the inhibitory projection from the MNTB - to compute interaural level (or volume) difference (ILD). The MNTB also provides a powerful inhibition to the Superior Paraolivary Nucleus (SPN) which is concerned with detecting the end of a sound or gaps in sounds (see research projects). The common feature of auditory processing in this region is fast and accurate transmission of information as action potential trains. This enhances comparison of sound between both ears for the physiological functions of sound localisation in auditory space, for feature extraction in a noisy environment and for computation of temporal features, such as gap detection.

Brainstem Auditory Pathway

2. Hearing loss – Disease mechanisms in the auditory pathway. It is well established that loud sounds cause deafness by damaging hair cells in the cochlea; but extreme activation also triggers plasticity in the brains at the synapses and neurons of the auditory pathway and this can damage the brain itself. For example, we have recently shown that loud sounds change the expression of the glutamate receptor subunit genes, so as to favour synaptic channels with slower gating. We have also conducted two different types of experiment to examine the mechanisms of deafness. Sherylanne Newton is examining the changes in gene expression (RNA sequencing) following exposure to damaging levels of sound. We hope this will give us insights into changes associated with ageing and hearing loss. Second, Drs Emanuele Schiavon and Josh Smalley are studying how accumulation of bilirubin (such as happens in jaundice or with liver damage) causes deafness and demonstrated that this is associated with synaptic damage and induction of inflammatory signaling in the brain.

 

Image3_Cochelar-hair-cells.gif

 

Hair cells are aligned along the length of the cochlea to sense sound.

3. The calyx of Held. This is the largest synapse in the brain and we developed the means to make direct recordings from it (Forsythe, 1994); this allowed the study of presynaptic calcium channels and transmitter release (exocytosis) at this glutamatergic synapse. In collaboration with Dr Vincenzo Marra we are examining vesicle recycling at the calyx of Held and it’s modulation by presynaptic mechanisms. Dr Sarah Lucas is using simultaneous presynaptic and postsynaptic recording to examine how differences in metabolic substrates (such as glucose and lactate) influence transmission at the calyx. This has implications for understanding the metabolic constraints on information transmission at all synapses in the brain. This is also part of a wider collaboration with computational neuroscientists Drs Bruce Graham, Matthias Hennig and Christophe Michel.

 

Image4_Calyx-of-Held.gif

 

The Calyx of Held is shown enclosing a single MNTB neuron. All three images are from one synapse (scale bar is 10 micrometers); the left and the right images are projections of the upper and lower halves of the giant synapse. The middle image is a single optical section through the ‘equator’: the ‘hole’ in the middle in the unstained MNTB neuron which is receiving input from one giant synapse (coloured red).

Background - the Calyx of Held: a model excitatory synapse

This giant synapse was first discovered by the German anatomist Hans Held, who studied in Leipzig and first published his anatomical study of the central auditory pathway in 1893. One Hundred years later we were attempting to make electrophysiological recordings from this living synapse using an in vitro preparation.

The Calyx of Hans Held

4. Potassium channels and intrinsic excitability. We have a long interest in understanding the physiological role of different voltage-gated potassium channels and in explaining why there are more than 80 potassium channel subunit genes. Our recent work has focused on Kv2 and Kv3 families. Kv2 is the major delayed rectifier of the neocortex and is highly clustered and controlled by phosphorylation. Kv3 is responsible for generating very short action potentials; we have examining which subunit genes are expressed in the auditory brainstem and their role in auditory processing. Both Kv2 and Kv3 channels are modulated by nitric oxide (NO, which is generated by synaptic activity). NO suppresses Kv3 channels and facilitates Kv2, thereby switching the basis of action potential repolarization in the MNTB (Steinert et al., 2011). These modulatory mechanisms are thought to underlie the control of neuronal excitability – by a process called ‘intrinsic plasticity’. This is where synaptic inputs up- or down-regulate the neuronal potassium currents, so as to harmonize excitability to the overall synaptic activity. We are studying these signaling mechanisms in the brainstem and neocortex, where these processes are postulated to underlie pathological processes such as tinnitus and stroke.

 

Image5_Brainstem_Kv_smaller.gif

 

The auditory brainstem expresses different combinations of potassium channel genes in each nucleus. Here the image shows fluorescent antibodies labelling the potassium channel subunits Kv3.1 (in green) and Kv2.2 (in red).

Publications

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

T: +44 (0)116 252 2922
E: npbenquiries@le.ac.uk