Endocytosis and lysosomal degradation of GluA2/3 AMPARs in response to oxygen/glucose deprivation in hippocampal but not cortical neurons

Abstract Global cerebral ischemia results in oxygen and glucose deprivation (OGD) and consequent delayed cell death of vulnerable neurons, with hippocampal CA1 neurons more vulnerable than cortical neurons. Most AMPA receptors (AMPARs) are heteromeric complexes of subunits GluA1/GluA2 or GluA2/GluA3, and the presence of GluA2 renders AMPARs Ca2+-impermeable. In hippocampal CA1 neurons, OGD causes the synaptic expression of GluA2-lacking Ca2+-permeable AMPARs, contributing to toxic Ca2+ influx. The loss of synaptic GluA2 is caused by rapid trafficking of GluA2-containing AMPARs from the cell surface, followed by a delayed reduction in GluA2 mRNA expression. We show here that OGD causes endocytosis, lysosomal targeting and consequent degradation of GluA2- and GluA3-containing AMPARs, and that PICK1 is required for both OGD-induced GluA2 endocytosis and lysosomal sorting. Our results further suggest that GluA1-containing AMPARs resist OGD-induced endocytosis. OGD does not cause GluA2 endocytosis in cortical neurons, and we show that PICK1 binding to the endocytic adaptor AP2 is enhanced by OGD in hippocampal, but not cortical neurons. We propose that endocytosis of GluA2/3, caused by a hippocampal-specific increase in PICK1-AP2 interactions, followed by PICK1-dependent lysosomal targeting, are critical events in determining changes in AMPAR subunit composition in the response to ischaemia

Receiving operating characteristics (ROC) curve for the selected echocardiographic parameters in relation to the peak VO2 values.

<p>Receiving operating characteristics (ROC) curve for the selected echocardiographic parameters in relation to the peak VO2 values.</p

Receiving operating characteristics (ROC) curve for the selected echocardiographic parameters in relation to the peak VO2 values.

<p>Receiving operating characteristics (ROC) curve for the selected echocardiographic parameters in relation to the peak VO2 values.</p

Conventional two-dimensional echocardiography parameters in the investigated groups.

<p>Conventional two-dimensional echocardiography parameters in the investigated groups.</p

Correlation between the parameters of cardiopulmonary exercise testing and echocardiographic parameters.

<p>Correlation between the parameters of cardiopulmonary exercise testing and echocardiographic parameters.</p

Demographic characteristics and clinical parameters of the study population.

<p>Demographic characteristics and clinical parameters of the study population.</p

Two–and three-dimensional speckle tracking echocardiography parameters in the investigated groups.

<p>Two–and three-dimensional speckle tracking echocardiography parameters in the investigated groups.</p

Receiving operating characteristics (ROC) curve for the selected echocardiographic parameters in relation to the VE/VCO2 slope values.

<p>Receiving operating characteristics (ROC) curve for the selected echocardiographic parameters in relation to the VE/VCO2 slope values.</p

The six-factor model of the SATS 36 (standardized parameter estimates).

<p>The six-factor model of the SATS 36 (standardized parameter estimates).</p

Regression models of variables associated with student attitudes towards statistics.

<p>*For n = 141 students; GPA = Grade Point Average.</p><p>Regression models of variables associated with student attitudes towards statistics.</p