Abnormalities in the connectivity and activity of the prefrontal cortex (PFC) is the cause of many of the symptoms of neuropsychiatric disorders such as schizophrenia and Alzheimer’s disease. The PFC relies on a complex regulation of network activity and synaptic plasticity for healthy PFC function. These fundamental processes can be modulated by the neuromodulator acetylcholine, acting at α7 nicotinic acetylcholine receptors (α7 nAChRs), a system also compromised in neuropsychiatric disorders. Despite the evidence that α7 nAChRs are essential for healthy PFC function relatively little is known about how activity at this receptor can modulate the fundamental network activity and synaptic plasticity within the PFC. This thesis aims to address some of these issues by using brain slice electrophysiology to measure network activity and synaptic plasticity in response to α7 nAChR activity within the prelimbic cortex (PrL) of C57BL/6J mice. Extracellular field recordings revealed that the selective α7 nAChR antagonist MLA, can reduce and enhance the levels of stimulus- induce long-term potentiation (LTP) and depression (LTD) respectively. In contrast global activation of α7 nAChRs with the selective α7 nAChRs agonist PNU-282987 and positive allosteric modulator PNU-120596 also reduced the levels of LTP. To provide a mechanism for these observations, whole-cell patch clamp recordings were carried out. These experiments revealed that α7 nAChRs reside presynaptically on glutamate inputs and somatodendritically on non-fast-spiking inhibitory interneurons enabling them to enhance both excitation and inhibition in a dynamic way. Further work demonstrated that tonic endogenous ACh acting at α7 nAChRs preferentially enhances excitation rather than inhibition. To further investigate if presynaptic α7 nAChRs were expressed selectively on a subset of the many afferent fibres connecting to the PrL, optogenetic methodologies were used to selectively evoke glutamate release from discrete afferent inputs, these experiments revealed α7 nAChRs may potentially reside on thalamic inputs to the PrL.
|Date of Award||23 Nov 2016|
|Supervisor||Chris Bailey (Supervisor) & Sue Wonnacott (Supervisor)|