Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines

Memories are formed at structures in the brain known as dendritic spines. These structures receive connections from other brain cells through regions called synapses. In humans, the number of these brain connections increases dramatically from birth to childhood, reflecting a period of rapid learning. However, the number of these brain connections halves after puberty, a dramatic reduction shown in many brain areas and for many species, including humans and rodents. This process is referred to as adolescent synaptic pruning and is thought to be important for optimal learning in adulthood because it is disrupted in autism and schizophrenia. Synaptic pruning is believed to remove unnecessary brain connections to make room for new relevant memories. However, the process that triggers synaptic pruning is not known. Within the brain, proteins called inhibitory GABA receptors are targets for chemicals that reduce the activity of nerve cells. As brain connections must be kept active to survive, inhibitory receptors could help to trigger synaptic pruning. Afroz, Parato et al. now show that, at puberty, the number of a particular type of GABAA receptor increases in the brain of female mice. This triggers synaptic pruning in the hippocampus, a key brain area necessary for learning and memory. By reducing brain activity, these inhibitory receptors also reduce the levels of a protein in the dendritic spine that stabilizes the scaffolding of the spine to maintain its structure. Mice that do not have these GABAA receptors maintain a constant high level of brain connections throughout adolescence, and synaptic pruning does not occur in their brains. These mice were initially able to learn to avoid a specific location that provided a mild shock to their foot. However, when this location changed the mice were unable to re-learn where to avoid, suggesting that too many brain connections limits learning potential. Brain connections are regulated by many factors, including the environment and stress. Future studies will test how these additional factors alter synaptic pruning in adolescence, and will test drugs that target these inhibitory receptors to manipulate adolescent pruning. These findings may suggest new treatments for “normalizing” synaptic pruning in conditions where this process occurs abnormally, such as autism and schizophrenia.