Applicant for Position of Director, Eccles Institute for Neuroscience.
Professor Ian D Forsythe, Department of Cell Physiology & Pharmacology, University of Leicester.
Host: Julio Licinio
My group is broadly interested in how ion channel conductances shape information transmission and integration in identified neurons. This requires that we focus on pathways with known physiological function; hence our interest in the brainstem auditory pathway, auditory processing and sound-source localisation. We define ion channel subunit expression, use pharmacological and molecular techniques to equate this with an ionic conductance and then relate this to roles in neuronal excitability. The auditory brainstem also possesses a giant synapse, with transmission mediated by the global transmitter glutamate that (arguably) has become the synapse at which we best understand mechanisms of exocytosis. What we learn about ion channel function in the brainstem is also applicable to higher brain centres.
Our recent focus has been on the ionic mechanism(s) by which nitric oxide modulate neuronal function through increasing and/or decreasing activity of different families of potassium (K+) currents. Principle neurons of the medial nucleus of the trapezoid body (MNTB, which receive the giant calyx of Held synapse) express K+ channels from Kv1, Kv2, Kv3 & Kv4 families; each has a different role in regulating the target neuron excitability during sound activation. Activation of the calyx of Held synapse not only generates a large synaptic current, but also stimulates Ca2+-dependent neuronal nitric oxide synthase (nNOS) so that downstream NO signalling suppresses Kv3 currents and potentiates Kv2 currents. This switches the basis of action potential repolarization (delayed rectification) and enhances the ability of these relay neurons to maintain high frequency firing during periods of high activity. This has several broader consequences: first – this signalling mechanism is also present in the hippocampus; second, spontaneous levels of synaptic activity can generate NO modulation of excitability; third, this implies that neuronal intrinsic excitability is plastic and tuned to the strength of synaptic activity.
I completed my PhD on primary afferent depolarization (PAD) using an in vitro spinal cord preparation at the University of Southampton in 1983 and my first postdoc was with Steve Redman here at the JCSMR. In 1985 I was awarded a Fogarty Fellowship to work in Phil Nelson’s laboratory in the NICHD, NIH (Bethesda, USA) where I and Gary Westbrook identified synaptic glutamate receptor subtypes. In 1988 I returned to the UK, Leicester, as a postdoc in Peter Stanfield’s group because I was keen to learn unitary channel recording and this is where I became so fascinated by potassium channels. In 1990 I was awarded a Wellcome Trust Fellowship in Basic Biomedical Sciences to study presynaptic ion channels and it was through this funding that I set up the auditory brainstem slice preparation and obtained the first recordings from the calyx of Held. In 1998 I became Reader and then in 1999, Chair of Neuroscience in the Department of Cell Physiology and Pharmacology, with research funding from the Wellcome Trust, MRC and BBSRC. In 2005 I moved to the MRC Toxicology Unit as Group Leader of the group: Neurotoxicity at the Synaptic Interface. This intramural funded post allowed us to focus on nitrergic signalling, toxicity and injury in the auditory brainstem. Last year I moved back into the University as Chair of Neurophysiology and I have recently taken over as leader of the Neuroscience & Behaviour Theme of the Medical College.
My laboratory considers how synaptic transmission and ion channels contribute to auditory processing; the role(s) of Nitric Oxide as a volume transmitter and retrograde messenger in the brain; and homeostatic regulation of voltage-gated potassium channels, neuronal excitability and intrinsic plasticity. These processes underlie normal function and disease; for example, we have a particular interest in how loud sounds (and toxic molecules) contribute to hearing loss by causing brain injury.