Altered gene expression profiles in the hippocampus and prefrontal cortex of type 2 diabetic rats

Abstract

BackgroundThere has been an increasing body of epidemiologic and biochemical evidence implying the role of cerebral insulin resistance in Alzheimer-type dementia. For a better understanding of the insulin effect on the central nervous system, we performed microarray-based global gene expression profiling in the hippocampus, striatum and prefrontal cortex of streptozotocin-induced and spontaneously diabetic Goto-Kakizaki rats as model animals for type 1 and type 2 diabetes, respectively.ResultsFollowing pathway analysis and validation of gene lists by real-time polymerase chain reaction, 30 genes from the hippocampus, such as the inhibitory neuropeptide galanin, synuclein gamma and uncoupling protein 2, and 22 genes from the prefrontal cortex, e.g. galanin receptor 2, protein kinase C gamma and epsilon, ABCA1 (ATP-Binding Cassette A1), CD47 (Cluster of Differentiation 47) and the RET (Rearranged During Transfection) protooncogene, were found to exhibit altered expression levels in type 2 diabetic model animals in comparison to non-diabetic control animals. These gene lists proved to be partly overlapping and encompassed genes related to neurotransmission, lipid metabolism, neuronal development, insulin secretion, oxidative damage and DNA repair. On the other hand, no significant alterations were found in the transcriptomes of the corpus striatum in the same animals. Changes in the cerebral gene expression profiles seemed to be specific for the type 2 diabetic model, as no such alterations were found in streptozotocin-treated animals.ConclusionsAccording to our knowledge this is the first characterization of the whole-genome expression changes of specific brain regions in a diabetic model. Our findings shed light on the complex role of insulin signaling in fine-tuning brain functions, and provide further experimental evidence in support of the recently elaborated theory of type 3 diabetes.

Ethanol-related alterations in gene expression patterns in the developing murine hippocampus

“…Gal is an inhibitory neuropeptide that is widely expressed in the central and peripheral nervous systems in vertebrates [29]. It co-exists within neurons with several small molecular classical neurotransmitters [30] and exerts strong inhibitory actions on synaptic transmission by reducing the release of neurotransmitters [31,32].…”

“…It has been previously reported that Gal shows distinct up-regulation after pathological disturbance within the nervous system, such as peripheral nerve injury [33]. Moreover, improvement of cognitive functions has been reported in animals treated with Gal receptor antagonists [29]. The formation of the mammalian central nervous system requires the establishment of complex neural circuits between diverse arrays of neuronal subtypes.…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…A recent whole-genome profile study revealed that 30 genes from the hippocampus, including galanin, and 22 genes from the prefrontal cortex, including GAL 2 , were found to exhibit altered expression levels in type 2 diabetic rats compared with nondiabetic control rats, shedding further light on the complex role of insulin signaling in fine-tuning brain functions and its interactions with galanin systems (Abdul-Rahman et al, 2012).…”

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

“…Moreover, compared to non-diabetic Wistar rats, also non-obese insulin-resistant Goto-Kakizyki (GK) rats displayed reduced spatial memory, which was accompanied by reduced pre-synaptic markers and increased glial specific proteins in the hippocampus [131]. Altered expression of genes involved in neurotransmission (among others) was found in the cortex of GK rats [132], indicating that diabetes-induced synaptic alterations are not region specific. A recent publication also reported that, relative to controls, GK rats display learning and memory deficits in a Morris water maze that are proportional to the grade of insulin resistance, reduction in dendritic spine density and neuronal viability in CA1 of the hippocampus, and impaired insulin-stimulated Akt/CREB phathway [133], consistent with AD-like pathology.…”