The Role of ADAP/Centaurin-A1 In Hippocampal-Based Trace Eyeblink Classical Conditioning

Abstract

The synaptic protein ADAP1/Centaurin-a1 (CentA1) is found in high concentrations within the brain. It is known to regulate dendritic differentiation and their structural plasticity. Research has shown that it may mediate Alzheimer’s disease (AD) pathogenesis, leading to behavioral and cognitive impairments in mice. CentA1 is upregulated by amyloid β (Aβ), which correlates with Aβ-dependent spine loss and deficits in spine plasticity in mice. In turn, plaques comprised of Aβ are highly associated with AD progression. Indeed, phosphorylation of CentA1 is prominently expressed in hippocampal tissues of AD patients. In this study we investigated whether suppression of CentA1 would be an ideal method to reverse cognitive dysfunction using trace eyeblink classical conditioning (TECC), a well-studied form of learning mediated by cortical-hippocampal interactions. A learning task that assesses this neural circuit is used because it is highly susceptible to AD neuropathogenesis. AD is characterized by progressive loss of many cognitive functions. Looking at CentA1 overexpression is a novel approach to understanding neuropathology of AD, as current treatments have yielded very little in terms of long-term efficacy. Elevated CentA1 may enhance AD progression and pathology, leading to cognitive impairments and its reduction is a potential target for experimental therapeutics. Adult male and female wild-type (WT) and CentA1 knockout (KO) mice were surgically implanted with recording electrodes and a stimulating electrode. After recovery, they received six days of TECC. Each day consisted of 100 trials in which a 380-ms, 80 dB tone conditioned stimulus (CS) was paired with a 100-ms, 1.6 mA current (unconditioned stimulus, US) delivered to the periorbital muscle to elicit an eyeblink unconditioned response (UR). A trace period of 500 ms in between the tone CS and shock US was imposed. The learning measure is the conditioned response (CR), an anticipatory eyeblink that is elicited by the tone CS and is emitted prior to the US. The trace period taxes the ability to time events properly and requires the integrity of cortical-hippocampal circuits. We compared whether the learning curves expressed by each group differed significantly. Results from this study will provide novel insight on whether CentA1 plays a role in mediating adverse learning outcomes in AD.