A neurophysiological and proteomic study of cognitive enhancing strategies

[摘要] Improving cognitive function is a growing area of interest for pharmaceutical companies. With an ageing population, cognitive decline is becoming a greater problem. Understanding the physiological effects of nootropic drugs and the changes that occur during cognitive enhancement will enable the design of safer treatments to enhance cognition.In this thesis cognitive enhancing strategies are investigated using neurophysiological and proteomic approaches. The effects of two classes of putatively cognitive enhancing drugs on emergent network oscillatory activities in hippocampal slices are investigated. The effect of an enriched environment, which causes an improvement in cognitive function, on the expression level of proteins in the hippocampus is also investigated. The development of a new muscarinic acetylcholine receptor (mAChR) agonist that is selective for the M1 mAChR subtype, called 77-LH-281, has recently been achieved. 77-LH-281 binds to an allosteric site of the M1 mAChR which accounts for its increased selectivity over other mAChR agonists. This agonist causes gamma frequency oscillatory activity in hippocampal slices, a pattern of network activity that the in vivo equivalent of which is associated with cognitive processes. This gamma activity is dependent upon both excitatory and inhibitory networks. 77-LH-281 does not promote epileptiform-like activity in naïve slices as well as a range of models of epileptiform activity, unlike non-subtype selective mAChR agonists like oxotremorine-M. Oxotremorine-M changes the slow inter-ictal-like events following application of 4-AP and NBQX into continuous beta frequency oscillations. This action is not mediated by the M1 mAChR. Thus selective M¬1 mAChR display a preferable range of oscillatory activities compared to non-subtype selective mAChR agonists. Ampakines are a further class of nootropic drugs. Ampakines are positive modulators of AMPA-type glutamate receptors and they cause improvements in cognitive function of laboratory animals and humans. The ampakines investigated in this thesis are CX691, which increases the amplitude of currents through the AMPA receptor, and CX546, which increases the length of time the AMPA receptor is open. These ampakines do not induce oscillatory activity in naïve hippocampal slices, but they increase the frequency of inter-ictal-like epileptiform activity. CX546 also induces ictal-like activity in the 4-AP induced epileptiform event model. Ampakines may therefore promote epileptiform activity in individuals that are susceptible to epilepsy. Exposure to an enriched environment leads to improvements in cognitive performance. This behavioural change is mediated by changes at the level of the proteome. Exposure to an enriched environment changes the expression of many classes of proteins including signalling proteins and proteins that are involved in the structural changes that occur during cognitive enhancement. One of the proteins that significantly changes in expression is a protein that is associated with cognitive deficits, known as MeCP2. MeCP2 is a transcriptional repressor and increases in expression in the enriched environment. This thesis demonstrates the diversity of molecular, cellular and network level approaches that can be used to induce and investigate cognitive enhancement. A combination of these approaches enables the in vitro evaluation of current cognitive enhancing strategies and may lead to the the development of novel approaches to enhance cognitive function.

[发布机构] University:University of Glasgow;Department:Institute of Neuroscience and Psychology

[关键词] 77LH281, muscarinic receptors, hippocampus