Insulin receptor β-subunit haploinsufficiency impairs hippocampal late-phase LTP and recognition memory.
The insulin receptor (IR) is a protein tyrosine kinase playing a pivotal role in the regulation of peripheral glucose metabolism and energy homoeostasis. IRs are also abundantly distributed in the cerebral cortex and hippocampus, where they regulate synaptic activity required for learning and memory. As the major anabolic hormone in mammals, insulin stimulates protein synthesis partially through the activation of the PI3K/Akt/mTOR pathway, playing fundamental roles in neuronal development, synaptic plasticity and memory. Here, by means of a multidisciplinary approach, we report that long-term synaptic plasticity and recognition memory are impaired in IR β-subunit heterozygous mice. Since IR expression is diminished in type-2 diabetes as well as in Alzheimer's disease (AD) patients, these data may provide a mechanistic link between insulin resistance, impaired synaptic transmission and cognitive decline in humans with metabolic disorders.
IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano, 64/65, 00143, Rome, Italy. r.nistico@med.uniroma2.it
Robert
R
Nisticò
Virve
V
Cavallucci
Sonia
S
Piccinin
Simone
S
Macrì
Marco
M
Pignatelli
Bisan
B
Mehdawy
Fabio
F
Blandini
Giovanni
G
Laviola
Davide
D
Lauro
Nicola B
NB
Mercuri
Marcello
M
D'Amelio
D000544:Alzheimer Disease / Q000378:metabolism / Q000523:psychology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000523:psychology; D005260:Female; D006579:Heterozygote; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D007333:Insulin Resistance; D007859:Learning Disabilities / Q000235:genetics* / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000235:genetics*; D008569:Memory Disorders / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D057907:Post-Synaptic Density / Q000648:ultrastructure; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D021641:Recognition, Psychology; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse