Adiponectin alters hippocampal synaptic function: a mechanism for amelioration of synaptic deficits in a mouse model of Alzheimer’s disease

Abstract

The hormone adiponectin, the most abundant adipokine, is an important regulator of metabolic function, and recent evidence suggests that adiponectin plays an essential role in the cross-talk between adipose tissue and brain function. Additionally, adiponectin receptors in the brain may serve as novel targets for central nervous systems disorders, including Alzheimer’s disease (AD). In the current study, we provide evidence that adiponectin receptor signaling directly influences hippocampal synaptic function. First, we established that adiponectin receptors are located at the synapse, with AdipoR1 particularly enriched in the synaptic fraction. Next, we found that aged adiponectin knockout mice display deficits in behavioral tasks including novel object recognition. The behavioral alterations were mirrored by a reduction in hippocampal synaptic plasticity and basal synaptic transmission, and synaptic deficits were rescued by slice incubation with the adiponectin receptor agonist, AdipoRon. Our results, along with emerging results from other groups, suggested that adiponectin may support neuronal processes and that a reduction in adiponectin or adiponectin receptor signaling may lead to an AD-like pathology. Therefore, we hypothesized that activation of adiponectin receptors may rescue synaptic deficits in a mouse model of AD. We found evidence for dysregulation of adiponectin and AdipoR1 expression in the 3xTg AD model and that slice incubation in adiponectin or the adiponectin receptor agonist, AdipoRon, could rescue synaptic deficits. The rescue of some synaptic parameters by AdipoRon appeared to be via activation of 5' AMP-activated protein kinase (AMPK), and rescue was associated with alterations in glycogen synthase kinase beta (GSK3β) and glutamatergic receptors. Taken together, the results from the current study indicate that adiponectin receptor signaling influences hippocampal synaptic function. This work contributes to a growing body of evidence which suggests a therapeutic potential for adiponectin receptor agonists in the prevention or treatment of AD.