Outside the field of diabetes research, animal models are widely used to explore the mechanisms of learning and memory. Although many questions remain unanswered, much progress has been made in identifying the cellular and molecular events that underlie the storage of information in specific brain areas. In this respect, the hippocampus, a structure in the medial temporal lobe, has attracted particular attention. Within the hippocampus, activity-dependent plastic changes in the strength of synaptic connections between neurons can be studied in vivo and in vitro and serve as a model for information storage at the cellular level (1). Long-term potentiation (LTP) and depression (LTD) are two such forms of synaptic plasticity. In LTP, brief high-frequency
From: Contemporary Diabetes: Diabetic Neuropathy: Clinical Management, Second Edition Edited by: A. Veves and R. Malik © Humana Press Inc., Totowa, NJ
afferent activity leads to a long-lasting increase in the strength of synaptic transmission, whereas in LTD prolonged low-frequency activity results in a persistent reduction in synaptic strength. Both processes depend on glutamatergic neurotransmission and are triggered by an increase in the level of postsynaptic intracellular calcium concentration [Ca2+] (1). Experimental manipulations that disturb hippocampal synaptic plasticity, typically also disturb behavioral learning tasks, such as spatial learning in a water maze.
Several aspects of hippocampal function and structure have been studied in diabetic rodents to increase our understanding of the effects of diabetes on the brain. The majority of these studies have been performed in streptozotocin (STZ) diabetic rats, although the number of studies in spontaneously diabetic rodent models is increasing.
Studies of behavioral learning in STZ-diabetic rodents have used several learning tasks (2). Whereas performance on relatively simple passive or active avoidance tasks is generally preserved, performance on more complex learning tasks, such as an active avoidance T-maze, or a Morris water maze, is impaired (3,4). The development of learning deficits in the water maze is dependent on the duration of STZ-diabetes and the level of hyperglycemia (4,5). Subcutaneous implantation of insulin pellets at the onset of diabetes, leading to near normalization of blood glucose levels, completely prevents the learning deficit (5). If, however, insulin-treatment is started 10 weeks after diabetes onset, when learning is already impaired, there is only partial improvement (5). Control experiments show that these performance deficits are not because of sensorimotor impairment (4,5). Studies on water maze learning in spontaneously diabetic BB/Wor rats, or OLETF rats, produced similar results (6,7).
Learning deficits in STZ-diabetic rats develop in association with distinct changes in synaptic plasticity in hippocampal slices, which also appear to be dependent on diabetes duration and severity (2). A deficit in the expression of N-methyl-D-aspartate (NMDA)-dependent LTP in the Cornu Ammonis(CA)1 field of the hippocampus develops gradually and reaches a maximum at 12 weeks after diabetes induction (4,8,9). At this time-point, NMDA-dependent LTP in the dentate gyrus and NMDA-independent LTP in the CA3 field are also impaired (9). Insulin treatment prevents the development of the changes in LTP, but only partially reverses existing deficits (5). In contrast to LTP, expression of LTD is enhanced in the CA1 field following low-frequency stimulation of slices from diabetic rats (9).
A number of studies have tried to pinpoint the mechanisms underlying these alterations in hippocampal synaptic plasticity. In presynaptic fibers, subtle changes are detected, including reduced impulse conduction velocity (10). However, as paired-pulse facilitation in the CAl-field is unaffected (4), presynaptic function appears to be largely preserved. Therefore, it is likely that the plasticity deficit is mainly postsynaptic in nature, involving glutamate receptors, membrane excitability, and/or the intracellular signaling cascade involved in LTP and LTD induction (2). The effects of diabetes on postsynaptic glutamate receptors in the hippocampus have been the subject of several studies (11). In Sprague-Dawley rats, after 6-8 weeks STZ-diabetes, the affinity of glutamate for a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), but not for NMDA-receptors, is decreased (12). The reduced affinity for AMPA is associated with reduced levels of the GluRl subunit of the AMPA receptor (12), whereas the level of GluR2 and 3 in the hippocampus and cortex is unaffected (12). After 12 weeks of STZ-diabetes the levels of the NMDA receptor subunits NMDA receptor (NR)1 and NR2A are not changed, but there is a marked decrease (-40%) in NR2B (13). Furthermore, the phosphorylation of the NR2A/B subunits by Ca2+/calmodulin-depend-ent protein kinase II is reduced in diabetes (13). These NMDA receptor related changes are likely to be involved in the LTP deficits.
Evoked potentials are electrical field potentials as recorded on the scalp that are generated by specific brain structures in response to visual, auditory, or somatosensory stimuli. Measurements of the latencies of these evoked potentials can be used to study the efficiency of signal conduction in the brain, as a central equivalent of peripheral nerve conduction studies. As might be expected, in both STZ- and spontaneously diabetic rats the latencies of visual, auditory, and somatosensory evoked potentials are increased (14,15). However, unlike peripheral nerve conduction deficits, increases in evoked potential latencies take months, rather than weeks, to develop (14).
Long-term STZ-diabetes is associated with loss of neocortical neurons (16,17). In BB/Wor rats, loss of hippocampal neurons is observed after 8, but not after 2 months of diabetes duration (6). However, ultrastructural changes may occur much earlier, as retraction and simplification of apical dendrites of hippocampal CA3 pyramidal neurons can be demonstrated within 9 days of untreated STZ-diabetes (18).
Microvascular changes, not unlike those observed in other organ systems, have also been observed in the brain of diabetic rodents, including decreased capillary density (16) and thickening of capillary basement membrane (17).
Several of the metabolic and vascular disturbances that are implicated in peripheral neuropathy also appear to affect the brain (2,19). As in the periphery, excess glucose is converted to sorbitol and fructose, leading to increased levels of these molecules in the brain (20,21). In contrast to observations in peripheral nerves, cerebral myo-inositol levels are increased despite the increase in sorbitol level (21). The amounts of advanced glycation end products (AGEs) are also increased in the brain and spinal cord of diabetic rats (22,23), as are the byproducts of lipid peroxidation, indicative of oxidative damage (24,25). Furthermore, the activities of superoxide dismutase and catalase, enzymes involved in the antioxidant defence of the brain, are decreased (26,27).
In the light of the changes in synaptic plasticity it is of particular interest to note that diabetes also affects the levels of second messengers and the activity of protein kinases in the brain. In diabetic rats cerebral phosphoinositide and diacylglycerol levels appear to be decreased whereas the activities of protein kinases A and C are increased (28) and the activity of calcium/calmodulin dependent protein kinase II is decreased (13).
In addition to the aforementioned structural alterations in the cerebral microvascula-ture, functional vascular changes such as a reduction in cerebral blood flow also occur (29,30). Interestingly, treatment of diabetic rats with the angiotensin enzyme inhibitor enalapril not only prevents deficits in blood flow, but also in water maze learning and hippocampal synaptic plasticity (30), indicating that vascular disturbances may indeed play a role in the aetiology of cerebral dysfunction.
Insulin itself may also be involved. The brain has long been considered an "insulin-insensitive organ." However, insulin and its receptor are now known to be widely distributed throughout the brain, with particular abundance in defined areas, such as the hippocampus. Insulin appears to affect cerebral glucose utilization, and plays a role in the regulation of food intake and body weight (31). In addition insulin acts as a "neuromodulator," influencing the release and reuptake of neurotransmitters and learning and memory (32). Disturbances in insulin signaling pathways in the periphery and in the brain have recently been implicated in Alzheimer's disease (AD) and brain ageing (2,33). Ageing is associated with reductions in the level of insulin and the number of its receptors in the brain (34). In AD this age-related reduction in cerebral insulin levels appears to be accompanied by disturbances of insulin receptor signaling in the brain (34), leading to the suggestion that AD is an "insulin-resistant brain state" (35). Insulin also regulates the metabolism of P-amyloid and tau, two proteins that represent the building blocks of amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of AD (33). The significance of these recent insights for diabetes is yet unknown.
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...