Diabetes Volume 64, November 2015 3653

Fernanda G. De Felice1,2,3 and Christian Benedict4

A Key Role of Insulin Receptors in Memory

Diabetes 2015;64:3653–3655 | DOI: 10.2337/dbi15-0011

Since the discovery of insulin in 1922 (1), the skeletal mus- dopamine signaling (9). While an early study found that cle, adipose tissue, and liver are traditionally regarded as key NIRKO mice do not show major learning and memory insulin-sensitive organs (2). Evidence of insulin actions in impairment (10), the study by Kleinridders et al. (9) dem- the brain emerged more recently, approximately 35 years onstrated that deletion of insulin receptors led to impor- ago, with studies showing that the hypothalamic actions tant defects in brain function. Therefore, further studies of insulin regulate peripheral energy homeostasis (reviewed contributing to the understanding of the role of insulin in [3]). Interestingly, insulin receptors were also detected in signaling in memory are definitely warranted. high densities in other brain regions (4), suggesting that In this issue of Diabetes, Grillo et al. (11) present their study insulin’s role in the central nervous system (CNS) extends of the role of hippocampal insulin receptor signaling in beyond hypothalamic control of energy homeostasis. neuroplasticity in rats by using a lentiviral vector expressing Thehippocampus,abrainregionkeytomemoryand an insulin receptor antisense sequence. Using this approach,

learning, was found to present particularly high levels the authors were able to downregulate insulin receptors in COMMENTARY of insulin receptors, suggesting that insulin could play the hippocampus without affecting peripheral glucose homeo- a role in synaptic plasticity mechanisms and memory stasis, thereby generating a rat model of hippocampal-specific formation in rodents and humans. Indeed, studies using impaired insulin signaling. Interestingly, they showed that in vitro and in vivo experimental models indicated that these rats exhibited impaired hippocampal synaptic plasticity insulin regulates neuronal survival, acts as a growth and hippocampus-dependent spatial learning. Furthermore, factor, and regulates circuit function and plasticity hippocampal levels of GluN2B subunit and phosphorylated (reviewed in [5]). In cultured hippocampal neurons, in- GluA1 were reduced, providing molecular clues on how the sulin receptors present a punctate dendritic distribution deficits in synaptic transmission develop without proper hip- that is consistent with the presence of insulin receptors at pocampal insulin signaling. While levels of insulin receptors, synaptic compartments (6). In harmony with the pro- insulin-stimulated phosphorylation of the insulin receptors, posed role of insulin signaling in cognition, intranasal in- andphosphorylatedAktweredecreasedinthehippocampus sulin treatment—a method achieving direct CNS delivery of the lentiviral-exposed rats, it remains to be established if of insulin without invasiveness or major complications other key components of the insulin signaling pathway are (7)—improves memory in healthy adults, without chang- also compromised in this model. ing blood levels of insulin or glucose (reviewed in [8]). Thus,whilethebrainhadbeenonceconsideredan While these recent studies and others have started to insulin-insensitive organ, it is now clear that it is an im- unravel the actions of insulin signaling in the brain, the portant target for insulin actions. It is crucial to identify in precise actions of insulin in brain areas responsible for detail the signaling pathways used by insulin in the brain, as memory still remain underexplored. failure of those signals has been associated with brain A recent study provided an important advance in disorders, including Alzheimer disease (AD) (12). It is fur- this field by showing that specific deletion of brain insulin ther possible that brain insulinresistanceisamechanism receptors in mice (NIRKO mice) led to augmented anxiety leading to cognitive decline in patients with diabetes, who and depressive-like behavior (9). NIRKO mice further pre- are at a higher risk of developing dementia and AD (13). In sented brain alterations in mitochondrial morphology fact, patients with type 1 and 2 diabetes show structural and function, elevated oxidative stress, and decreased brain alterations and cognitive impairment (14), and it is

1Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Corresponding author: Fernanda G. De Felice, [email protected]. Janeiro, Rio de Janeiro, Brazil © 2015 by the American Diabetes Association. Readers may use this article as 2 ’ D Or Institute for Research and Education, Rio de Janeiro, Brazil long as the work is properly cited, the use is educational and not for profit, and 3 ’ Department of Biomedical and Molecular Sciences, Queen s University, King- the work is not altered. ston, Ontario, Canada See accompanying article, p. 3927. 4Department of Neuroscience, Uppsala University, Uppsala, Sweden 3654 Commentary Diabetes Volume 64, November 2015 becoming increasingly clear that diabetes is a threat to the in the brain plays a central role in synaptic plasticity and brain. The study by Grillo et al. (11) contributes to the un- learning. The challenge now is to identify in detail the mo- derstanding of how hippocampal insulin resistance may lecular mechanisms underlying brain insulin resistance and negatively influence brain function and may be linked to to determine if restoring brain insulin signaling might be cognitive decline (Fig. 1). helpful to circumvent synapse deterioration and memory Impaired insulin sensitivity has been linked to cognitive failure in AD and related disorders. deficits and structural and functional brain abnormalities in the elderly (15,16). Furthermore, lower levels of insulin and insulin receptors and altered levels of different components Funding. F.G.D.F. is supported by grants from the Human Frontier Science Program and the John Simon Guggenheim Memorial Foundation; the Brazilian of the insulin signaling pathways were described in AD hip- funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico pocampi, indicating that a scenario of brain insulin resis- and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de tance develops in AD (17). Hippocampal insulin signaling Janeiro; and the Canadian Institutes of Health Research (operating grant impairments were also described in animal models of AD MOP-38854). C.B. is supported by grants from the Novo Nordisk Foundation (5). As a result of these and other studies, defective brain and the Swedish Brain Foundation. insulin signaling is now regarded as an important character- Duality of Interest. No potential conflicts of interest relevant to this article istic of AD pathology. It is interesting to note that similar were reported. mechanisms leading to peripheral insulin resistance and References overall health decline in type 2 diabetes have been found 1. Banting FG, Best CH. The internal secretion of the pancreas. 1922. Indian J to cause brain insulin resistance and memory impairment in Med Res 2007;125:251–266 AD. Linking pathogenic mechanisms in the AD brain to 2. Cahill GF Jr. The Banting Memorial Lecture 1971. Physiology of insulin in mechanisms present in metabolic diseases provides a ratio- man. Diabetes 1971;20:785–799 nale for using antidiabetes agents as novel therapeutics in 3. Porte D Jr, Baskin DG, Schwartz MW. Insulin signaling in the central ner- AD and as a strategy to prevent cognitive decline in diabe- vous system: a critical role in metabolic homeostasis and disease from C. ele- tes. Supporting this view, recent studies in mice and mon- gans to humans. Diabetes 2005;54:1264–1276 key models of AD demonstrated that the use of exendin-4 4. 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Inflammation, defective insulin signaling, and — Figure 1 Proposed role of neuronal insulin signaling in synaptic mitochondrial dysfunction as common molecular denominators connecting type 2 plasticity and memory. This simplified scheme illustrates some of diabetes to Alzheimer disease. Diabetes 2014;63:2262–2272 the mechanisms by which impaired insulin signaling impacts syn- apse plasticity and function. A: In physiological conditions, insulin 14. Biessels GJ, Reijmer YD. Brain changes underlying cognitive dysfunction in receptors (InsRs) are present at synapses, and phosphorylation (P) diabetes: what can we learn from MRI? Diabetes 2014;63:2244–2252 of the InsRs and Akt reflects proper insulin signaling, which is linked 15. Benedict C, Brooks SJ, Kullberg J, et al. Impaired insulin sensitivity as indexed to phosphorylation of GluA1 and presence of GluN2B at synapses, by the HOMA score is associated with deficits in verbal fluency and temporal lobe B favoring synapse function and memory formation. : In pathological gray matter volume in the elderly. Diabetes Care 2012;35:488–494 conditions (e.g., diabetes, AD), decreased levels of InsRs and phos- 16. Willette AA, Bendlin BB, Starks EJ, et al. Association of insulin resistance phorylation of the InsRs and Akt suggest reduced insulin signaling, which may be linked to decreased levels of GluN2B and GluA1 with cerebral glucose uptake in late middle-aged adults at risk for alzheimer phosphorylation at synapses. Reduced insulin signaling ultimately disease. JAMA Neurol. 27 July 2015 [Epub ahead of print]. DOI: 10.1001/ leads to impaired synapse plasticity and function. jamaneurol.2015.0613 diabetes.diabetesjournals.org De Felice and Benedict 3655

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