| Summary: | This thesis focused on the spatiotemporal patterning of classical excitatory and inhibitory synaptic contacts accounting for the majority of cerebral cortical connections, in relation to ageing and cognitive status. These investigations tested the hypothesis that higher CNS functions depend on the balance between excitatory and inhibitory synaptic connections. Glutamatergic and GABAergic presynaptic bouton densities were determined in aged animals segregated according to their cognitive status into aged and cognitively unimpaired (AU) and aged and cognitively impaired (AI), using the Morris water maze. These two groups were compared in terms of behaviour and the pattern of excitatory and inhibitory synapses. It was evident that an excitatory and inhibitory presynaptic decline is associated with age-related cognitive impairments; whereby both glutamatergic and GABAergic boutons gradually diminish from young to AU to AI. Nevertheless, the balance between excitatory and inhibitory presynaptic inputs was maintained. To determine whether postsynaptic sites differed with respect to ageing and cognitive impairments, excitatory and inhibitory postsynaptic scaffold proteins were investigated in the same cohort of segregated aged animals. There was an imbalance in density ratio between immunoreactive sites of excitatory versus inhibitory postsynaptic scaffold proteins in AI animals. This resulted from a marked decrease in the density of excitatory postsynaptic sites. To further investigate ultrastructural aspects of excitatory synapses I carried out electron microscopical studies of cerebral cortex to measure the abundance of NR2 receptor subunits of the NMDA receptor- a receptor site directly associated with excitatory postsynaptic scaffold proteins. This study revealed that NR2 immunoreactive sites were largely preserved during age-related cognitive decline with an uneven profile distribution. Finally, protein expression of specific receptor subunits and key proteins representative of excitatory and inhibitory postsynaptic sites was investigated by semi-quantitative Western blot analyses in selected cortical areas. It was clear that many of these postsynaptic proteins are affected by age and cognitive status. The most striking change was a marked up-regulation in neuroligin-1 in AI animals, which may affect the delicate balance between excitatory versus inhibitory synaptic inputs. Another notable finding was the down-regulated expression of GluR2 receptor subunits in AI animals, which should have implications for neuronal Ca2+ regulation. In conclusion, we have demonstrated the greater vulnerability of excitatory postsynaptic sites in aged and cognitively impaired animals.
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