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Inhibitory and excitatory synapse dynamics in the brain

Photo: Len Rubenstein

The brain adapts to the environment in part by persistently modifying and rearranging the diverse synaptic connections between neurons. These changes include strengthening or weakening existing links, as well as forming and eliminating synapses — long-term adjustments that are required for learning and memory.

Since excitatory synapses on excitatory neurons are localized to small protrusions called dendritic spines, earlier studies have used dendritic spine dynamics to monitor excitatory synaptic remodeling in vivo. However, the lack of a morphological surrogate for inhibitory synapses has precluded their observation, and although the interplay between excitatory and inhibitory transmission maintains a critical role in brain plasticity, the inability to monitor inhibitory synapse dynamics has prohibited examination of how they correspond with excitatory changes.

Sensory input impacts synapse activity

A new study co-authored by Elly Nedivi, Picower Institute for Learning and Memory, her students Jerry Chen and Katherine Villa from the Department of Biology, and colleagues Jae Won Cha and Peter So from the Department of Mechanical Engineering at MIT, as well as collaborator Yoshiyuki Kubota from the National Institute for Physiological Sciences in Japan, characterizes the distribution of inhibitory synapses across the brain’s neurons and shows that they are divided into two populations, one on dendritic spines adjacent to an excitatory synapse, the other on the dendritic shaft. They then measured the remodeling kinetics of the two populations during normal and altered sensory experience.

Researchers simultaneously monitored inhibitory synapses and dendritic spines across brain neurons using high-resolution dual-color two-photon microscopy. Their findings indicate that inhibitory spine and shaft synapses respond differently during normal and altered visual sensory experience, and when the inhibitory synapses and dendritic spines of cortical neurons are rearranged, they are locally clustered, based on sensory input. This work is slated to appear in the April 26 issue of Neuron.

To date, the distribution of inhibitory synapses on cell dendrites was estimated via volumetric density measurements. The new MIT study, however, demonstrates uniform distribution of inhibitory shaft synapses — versus spine synapses, which are twice as abundant along distal apical dendrites — suggesting that the two types of synapses have different roles in shaping dendritic activity. The differential distribution of inhibitory spine and shaft synapses may reflect their influence on the integration of calcium input from various sources.

Kinetic and clustering distinctions between synapse types

The research team also discovered that both synapse types are dynamic, but inhibitory spine synapses are fourfold more dynamic than their shaft counterparts. Monocular deprivation (MD), a visual paradigm for plasticity, resulted in a significant but transient loss of inhibitory spine synapses during the first two days of MD, while loss of shaft synapses persisted for at least four days. This demonstrates the impact of altered sensory experience and the kinetic distinction between the two synapse populations.

Next, the scientists looked for evidence of local clustering between excitatory and inhibitory synaptic changes during normal visual experience by performing analyses on dynamic and stable inhibitory synapses and spines. They found that inhibitory synapse changes occur in closer proximity to dynamic dendritic spines as compared to stable spines, and dendritic spine changes occur in closer proximity to dynamic inhibitory synapses as compared to stable ones. Researchers also demonstrated that this clustering pattern between dynamic inhibitory synapses and dendritic spines was enhanced by MD.

The researchers also proved that the percent of clustered dynamic spines and inhibitory synapses in response to MD is significantly higher than would be expected simply based on an increased presence of dynamic inhibitory synapses. “This suggests that while MD does not change the overall rate of spine turnover on cortical neurons, it leads to a greater coordination of these events with dynamics of nearby inhibitory synapses,” Nedivi explains.

New insights reveal potential impact on long-term memory

The ability of the MIT researchers to distinguish inhibitory spine and shaft synapses provides new insight into inhibitory synapse dynamics in the adult visual cortex. The inhibitory synapse losses that occur during altered visual experience, noted above, are consistent with findings that visual deprivation produces a period of disinhibition in the visual cortex.

In addition, the results of this MIT study provides evidence that experience-dependent plasticity in the brain is a highly orchestrated process, integrating changes in excitatory connectivity with the active elimination and formation of inhibitory synapses. This sheds new light on the importance of coordinating excitatory and inhibitory circuitry to help nurture long-term memory.

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