Somatostatin neurotransmission : studies on experimentally induced cognitive changes and Alzheimer’s disease

Abstract

Several neuropeptides are widely distributed in regions of the central nervous system (CNS) which are associated with cognitive functions. Multiple studies on postmortem Alzheimer's disease (AD) brains have shown depleted neuropeptide content and morphological abnormalities of somatostatin (SS)-containing interneurons in the hippocampus and the cerebral cortex. The present work have addressed questions on aspects of somatostatin neurotransmission in higher cognitive functions using AD postmortem material and by studying dynamic changes in the 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, however remaining receptors appeared functionally preserved in terms of G-protein uncoupling and SS-mediated signal transduction via the adenylate cyclase system (Study I).

Excitotoxic lesion of the nucleus basalis magnocellularis (NbM) with ibotenic acid transiently decreased neocortical SS receptor binding densities indicating that a subpopulation of SS receptors is located on cholinergic afferents. These results might suggest that SS-receptor downregulation in AD is associated with cholinergic degeneration (Study II).

Aged rats displayed decreased number of detectable preproSS-mRNA expressing cell bodies in the frontal cortex, 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 cognitive stimulation 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. Thus the increased SS levels had a degree of neurochemical specificity, although cognitive stimulation was not a prerequisite for these changes to appear (Study V).

Cognitive stimulation of impoverished animals shifted the composition of SS-immunoreactive species from the precursor (proSS) towards the maturated fragments (SS-2~ and SS-14) suggesting that the increased peptide levels were caused by a post translation mechanism, most probably through increased prohormonal processing (Study VI).

The present studies indicate a partial localization of SS receptors on afferents of cholinergic projection neurons from the NbM, which are closely associated with geriatric cognitive deficits. Furthermore a considerable sensitivity of cortical SS peptide levels to environmental manipulations was observed, particularly in the posterior part of the cerebral cortex with pronounced sensory terminal fields. Although not proving any causal link between SS and cognitive function this could be interpreted as involvement in neuronal plasticity. Since SS receptors appear relatively preserved with aging and AD pathology, both in number and function, retained functional abilities following support given in a rich sensory environment to dementia patients with preserved sensorimotor receptivity might be associated with effects exerted by cortical SS.