Brain stiffness changes in response to injury or disease. As a secondary consequence, glutamate is released from neurons and astroglia. Two types of glutamate receptors, N-methyl-d-aspartate (NMDA) and -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, sense mechanotransduction, leading to downstream signaling in neurons. Recently, our group reported that these two receptors affect dendrite morphology in hippocampal neurons grown on compliant substrates. Blocking receptor activity has distinct effects on dendrites, depending on whether neurons are grown on soft or stiff gels. In the current study, we examine whether exposure to glutamate itself alters stiffness-mediated changes to dendrites in hippocampal neurons. We find that glutamate augments changes seen when neurons are grown on soft gels of 300 or 600 Pa, but in contrast, glutamate attenuates changes seen when neurons are grown on stiff gels of 3,000 Pa. These results suggest that there is interplay between mechanosensing and glutamate receptor activation in determining dendrite morphology in neurons. (c) 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:1128-1132, 2015