Modulation of stretch-induced enhancement of neuronal NMDA receptor current by mGluR1 depends upon presence of glia

Stretching of cultured neurons has been used to model diffuse axonal injury associated with brain trauma. N-Methyl-D-aspartate receptor (NMDAR) activation and group I metabotropic glutamate receptors (mGluRs) are implicated in the pathophysiology of such injury. Here we detail the effects of culture condition and mGluR1 modulation on stretch-enhanced NMDA receptor activity, and show the presence of mGluR1 in addition to mGluR5 in glia. In cortical neurons grown in the absence (PN) or presence (NG) of a glial monolayer, stretch injury (5.7 mm) enhances NMDAR activity by increasing maximal NMDAR current, decreasing the voltage-dependent Mg2+ block, and altering the kinetic behavior of these receptors. In PN cultures, activation of mGluR1 increases stretch-enhanced NMDAR activity, whereas in NG cultures, such activity is reduced. In contrast, inhibition of mGluR1 in PN cultures limits stretch-enhanced NMDAR activity, whereas in NG cultures activity is increased. MGluR1 modulate stretch-enhanced NMDAR activity through multiple mechanisms including: altering peak or steady state current, affecting Mg2+ blockade of the NMDAR, or by changing NMDAR kinetics. The presence of glia significantly alters the nature of mGluR1-mediated modulation of NMDAR activity and stretch-induced injury. Together these data indicate a significant neuronal/glial interaction between glial mGluR1 and neuronal NMDA receptor activity.