MET receptor tyrosine kinase promotes the generation of functional synapses in adult cortical circuits

Abstract

Loss of synapse and functional connectivity in brain circuits is associated with aging and neurodegeneration, however, few molecular mechanisms are known to intrinsically promote synaptogenesis or enhance synapse function. We have previously shown that MET receptor tyrosine kinase in the developing cortical circuits promotes dendritic growth and dendritic spine morphogenesis. To investigate whether enhancing MET in adult cortex has synapse regenerating potential, we created a knockin mouse line, in which the human MET gene expression and signaling can be turned on in adult (10–12 months) cortical neurons through doxycycline-containing chow. We found that similar to the developing brain, turning on MET signaling in the adult cortex activates small GTPases and increases spine density in prefrontal projection neurons. These findings are further corroborated by increased synaptic activity and transient generation of immature silent synapses. Prolonged MET signaling resulted in an increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-D-aspartate (AMPA/NMDA) receptor current ratio, indicative of enhanced synaptic function and connectivity. Our data reveal that enhancing MET signaling could be an interventional approach to promote synaptogenesis and preserve functional connectivity in the adult brain. These findings may have implications for regenerative therapy in aging and neurodegeneration conditions.

Keywords

• aging
• circuit connectivity
• cortical circuits
• molecular mechanisms
• neural regeneration
• neurodegeneration
• synapses