Gas7 is a novel dendritic spine initiation factor.

Brain stores new information by modifying connections between neurons. When new information is learnt, a group of neurons gets activated and they are connected to each other via synapses. Dendritic spines are protrusions along neuronal dendrites where excitatory synapses are located. Dendritic spines are the first structures to protrude out from the dendrite to reach out to other neurons and establish a new connection. Thus, it is expected that neuronal activity enhances spine initiation. However, the molecular mechanisms linking neuronal activity to spine initiation are poorly known. Membrane binding BAR domain proteins are involved in spine initiation, but it is not known whether neuronal activity affects BAR domain proteins. Here, we used bicuculline treatment to activate excitatory neurons in organotypic hippocampal slices. With this experimental setup we identified F-BAR domain containing Growth Arrest-Specific Protein (Gas7) as a novel spine initiation factor responding to neuron activity. Upon bicuculline addition, Gas7 clustered to create spine initiation hotspots, thus increasing the probability to form new spines in activated neurons. Gas7 clustering and localization was dependent on PI3-kinase activity and intact F-BAR domain. Gas7 overexpression enhanced N-WASP localization to clusters as well as it increased the clustering of actin. Arp2/3 complex was required for normal Gas7-induced actin clustering. Gas7 overexpression increased and knockdown decreased spine density in hippocampal pyramidal neurons. Taken together, we suggest that Gas7 creates platforms under the dendritic plasma membrane which facilitate spine initiation. These platforms grow upon neuronal activation, increasing the probability of making new spines and new connections between active neurons. As such, we identified a novel molecular mechanism to link neuronal activity to the formation of new connections between neurons. Significance Statement When we learn something new, neurons change their connections to other neurons. We know that active neurons connect to each other, but we have poor understanding on the cellular or molecular mechanisms which link neuronal activity to the formation of new connections. Here we show how neuronal activation can facilitate formation of new connections to wire the firing neurons together.