Somatostatin neurotransmission : Studies on experimentally induced cognitive changes and Alzheimer's disease

Several neuropeptides are widely distributed in regions of the central nervous system (CNS) which are associatedwith cognitive functions. Multiple studies on postmortem Alzheimer's disease (AD) brains have shown depletedneuropeptide content and morphological abnormalities of somatostatin (SS)-containing interneurons in thehippocampus and the cerebral cortex. The present work have addressed questions on aspects of somatostatinneurotransmission in higher cognitive functions using AD postmortem material and by studying dynamic changes inthe somatostatin system in experimental models where cognitive alterations are evident. AD patients were found to have reduced 125I-Tyr11-SS-14 receptor densities in the frontal cortex, howeverremaining receptors appeared functionally preserved in terms of G-protein uncoupling and SS-mediated signaltransduction via the adenylate cyclase system (Study I). Excitotoxic lesion of the nucleus basalis magnocellularis (NbM) with ibotenic acid transiently decreasedneocortical SS receptor binding densities indicating that a subpopulation of SS receptors is located on cholinergicafferents. These results might suggest that SS-receptor downregulation in AD is associated with cholinergicdegeneration (Study II). Aged rats displayed decreased number of detectable preproSS-mRNA expressing cell bodies in the frontalcortex, while no changes in SS binding densities in cortical and hippocampal subregions were evident (Study III). Differential housing in enriched environment compared to impoverished environment, as well as cognitivestimulation of impoverished animals elevated cortical peptide SS levels but not preproSS-mRNA (Study IV). Sensorimotor stimulation of impoverished animals increased cortical SS levels to the same extent ascognitive stimulation, while neither of the environmental manipulations influenced cortical substance P levels. Thusthe increased SS levels had a degree of neurochemical specificity, although cognitive stimulation was not aprerequisite for these changes to appear (Study V). Cognitive stimulation of impoverished animals shifted the composition of SS-immunoreactive species fromthe precursor (proSS) towards the maturated fragments (SS-2~ and SS-14) suggesting that the increased peptidelevels were caused by a posttranslation mechanism, most probably through increased prohormonal processing(Study VI).The present studies indicate a partial localization of SS receptors on afferents of cholinergic projection neuronsfrom the NbM, which are closely associated with geriatric cognitive deficits. Furthermore a considerable sensitivityof cortical SS peptide levels to environmental manipulations was observed, particularly in the posterior part of thecerebral cortex with pronounced sensory terminal fields. Although not proving any causal link between SS andcognitive function this could be interpreted as involvement in neuronal plasticity. Since SS receptors appearrelatively preserved with aging and AD pathology, both in number and function, retained functional abilitiesfollowing support given in a rich sensory environment to dementia patients with preserved sensorimotor receptivitymight be associated with effects exerted by cortical SS.Keywords: Alzheimer's disease; Adenylyl cyclase; Autoradiography; Behavior; Cerebral cortex; Demenba;Environment; Ibotenic acid lesion; In-situ hybridization; Learning; Neuropeptides; Northern blot; Nucleus basalismagnocellularis; Posttranslational processing; Rat; Receptor; Signal transduction; Somatostatin