Role of nicotinic receptors in plasticity in the septohippocampal system

My project seeks to develop experimental models that mimic the natural release and binding of the chemical messenger acetylcholine to nicotinic receptors in the brain. This way I aim to gain a better understanding of how nicotinic receptors promote the molecular and cellular processes required for memory and learning.

In Alzheimer’s disease there is a progressive degeneration of brain regions underlying memory and cognition. One of the key brain areas affected in Alzheimer’s disease is that which produces and releases acetylcholine. Acetylcholinesterase is an enzyme that rapidly breaks down acetylcholine after it has been released in the brain. At present the main treatment for Alzheimer’s disease is with drugs that block the actions of acetylcholinesterase.

Acetylcholinesterase may, however, be especially important for the proper functioning of nicotinic receptors. This is because nicotinic receptors rapidly become paralysed if acetylcholine is not quickly removed after it has performed its signalling functions.

In my studies I will also aim to determine whether the anti-cholinesterase drugs used in Alzheimer’s disease disrupt the normal actions of acetylcholine on nicotinic receptors in memory and learning areas. The results should ultimately contribute towards the development of better therapeutic treatments for Alzheimer’s disease.

Nicotinic receptors possess important and specific functions in the CNS, e.g. in addiction and neuroplasticity, and their depletion in Alzheimer?s disease is believed to contribute towards the symptoms of dementia. The septum provides a major cholinergic input to the hippocampus via the septo-hippocampal pathway, and the septo-hippocampal system as a whole plays an essential role in the consolidation of memory via the generation of rhythmic activity and long potentiation. The precise mode of function of nicotinic receptors in these processes, however, is still far from clear. In the septo-hippocampal system there are several subtypes of nicotinic receptor located at specific synaptic as well as extrasynaptic locations, but nicotinic receptors are prone to desensitisation when investigated with bath applied nicotinic receptor agonists. The main hypothesis of this project is that to counteract desensitisation, acetylcholine (ACh) preferably acts on nicotinic receptors during burst firing of the cholinergic neurons. This theoretically would allow the delivery of intense packets of ACh to the receptors, and the neurotransmitter would then be rapidly broken down in between bursts by cholinesterase to prevent prolonged desensitisation. During these periods of episodic cholinergic activity ACh would then have the opportunity to interact with low affinity and high affinity nicotinic receptors to modulate network activity mediated by GABAergic and glutamate receptor transmission. If the burst firing activity is particularly intense or prolonged, this will cause long term changes in synaptic transmission via the lower affinity alpha7 nicotinic receptors which have a high level of permeability to calcium. These predictions will be tested on in vitro preparations of the septum and hippocampus. To mimic burst firing delivery of neurotransmitter, ACh solutions will be puffed onto the preparations by a computer controlled picospritzser. The main objectives of the proposed study will be to 1) to determine the role of nicotinic receptors in rhythmic activity and synaptic plasticity at GABAergic, glutamatergic and cholinergic synapses in the septohippocampal circuit; 2) modulation of these effects by anticholinesterases and other agents, and 3) ultrastructural localisation of nicotinic receptors in relation to identified neuronal structures, cholinesterase activity and second messenger systems by which the receptors could exert their roles in neuroplasticity.