Regulation of neuronal excitability and synaptic transmission by metabolic demand in health and disease

The brain uses vast metabolic resources to maintain electrical excitability and to integrate sensory information (Harris et al., 2012). However, the fundamental mechanisms by which brain activity can influence metabolic rate or how in diseases such as stroke (or dementias), compromised metabolism may influence information transmission are unresolved. Under physiological conditions, neurons normally adapt to bioenergetic challenges caused by ongoing activity in neuronal circuits; this signalling can induce compensatory expression of proteins to enhance resistance to metabolic, oxidative, excitotoxic, and proteotoxic stresses. During aging these mechanisms may become compromised, resulting in reduced cognitive performance in multiple domains including working and spatial memory and information processing. Similar changes can occur earlier in life during the development of neurological diseases. For instance, changes in nutrient transporter and metabolic enzyme expression levels and/or activities, have been reported in Alzheimer’s disease (AD); for example levels of glucose transporters GLUT1 and GLUT3 are reduced in the brains of AD patients (Simpson et al., 1994; Harr et al., 1995) which is associated with amyloid- signalling (Seixas da Silva et al., 2017) and correlates with diminished brain glucose uptake and subsequent cognitive decline (Landau et al., 2010).

This project will examine how the rates of information transmission (synaptic activity) influence downstream synapses in the brain and will explore the adaptations to ATP depletion and the functional consequences of metabolic limitation.

Our laboratory has extensive experience in the study of synaptic transmission, voltage-gated potassium channels and has ongoing projects concerning the metabolic regulation of neuronal excitability in information transmission. We have recently established that presynaptic ATP depletion during synaptic activity compromises specific steps of synaptic transmission by incorporating computational modelling with physiological measurements (Lucas et al., 2018). We conduct our studies in the auditory brainstem, because this region has a high metabolic rate and we have a well-established in vitro brain-slice preparation from which we can conduct in vitro electrophysiology, western blotting and immunohistochemistry. Patch recording and imaging methods will be used to monitor presynaptic [ATP] during high rates of synaptic transmission and when metabolic substrates are in limited supply. This novel approach to determine intracellular ATP levels uses a genetically expressed fluorescent indicator to image fluorescence-resonance energy-transfer (FRET). The main focus of the project will relate to metabolic dysfunction in stroke and neurodegenerative conditions as an underlying cause for disease and in relation to ageing.

The successful candidate will join a team of neuroscientists (see web site for further information) studying aspects of neuronal intrinsic plasticity and function, voltage-gated ionic currents and activity-dependent synaptic plasticity (Pilati et al., 2016).

Further information: http://www2.le.ac.uk/departments/npb/people/professor-ian-forsythe-1

Techniques that will be undertaken during the project
-In vitro brain slice preparation
-Patch clamp recording from neurons
-Calcium and ATP imaging
-Voltage-clamp
-Western blotting
-Immunohistochemistry
-Computational modeling