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The Role of Synaptic Density in Learning and Cognitive Function

How Does Synaptic Density Lends Itself to Faster Learning?

A large part of the brain’s activity depends on the proper formation and maintenance of synapses. Synaptic dysfunction is implicated in many psychiatric and neurodegenerative diseases.

It has been consistently reported that the neuropil is characterized by a higher number of excitatory than inhibitory contacts in different brain regions and species (Morales et al., 2013).

1. Synaptic Density Leads to Better Memory

The brain’s trillions of neurons communicate via millions of synapses. Among these, excitatory glutamate synapses exhibit the Hebbian form of plasticity that is central to memory formation and storage. Sculpting of these Hebbian synapses by the occurrence or absence of specific events is what causes memories to become permanent.

These excitatory synapses reside on dendritic spines, axon-dendrite connections that protrude from the cell’s surface. Spine formation, elimination, and morphological changes have been shown to correlate with learning in several paradigms. The efficacy of a spine’s synaptic transmission is determined by its morphology and the presence or absence of specific pre- and post-synaptic proteins (see Table 1).

Neuroscientist Peter Huttenlocher painstakingly counted thousands of these spines in electron micrographs of postmortem human brains from newborns to 90-year-olds. He found that synaptic density increases rapidly after birth, then drops during adolescence and stabilizes in adulthood. The reconstructed spines were further categorized using qualitative and quantitative parameters such as the length of the synaptic active zone, width of the cleft, and curvature of the synapse.

2. Synaptic Density Leads to Better Attention

The ability to detect paired-pulse facilitation or depression is a critical function for learning and memory. These forms of plasticity mainly result from changes in the probability of transmitter release (p). When a second stimulus is delivered within a short interval, synapses that begin with a high p tend to depress their response to the second pulse, while those with a low initial p exhibit facilitation. Manipulations that decrease p (eg, by decreasing the external concentration of calcium) relieve paired-pulse depression at many synapses.

Using scanning (sEM) electron microscopy, it is possible to determine the synaptic density of individual neurons. However, this technique requires thin tissue samples, complex preparation to avoid artifacts, and a highly specialized skill set for data acquisition and analysis.

In addition, the volume loss associated with AD could lead to underestimation of synaptic density. To address this, we performed our first-to-date EM study in individuals with normal cognitive abilities. We fit multiple linear regression models with global synaptic density measured by [11C]UCB-J as the predictor and performance on five separate cognitive domains (verbal memory, language, executive function, processing speed, visuospatial ability) as the outcome measure.

3. Synaptic Density Leads to Better Learning

The idea that the wiring of a brain is closely linked to its neural function and behaviour is hardly new, but advances in neuroimaging techniques have made it possible to collect direct empirical data linking synaptic density with cognitive performance and disease in living human brains.

For example, PET studies have shown that global synaptic density as measured by [11C]UCB-J DVR correlates with cognition in people with early Alzheimer’s dementia. In a multiple linear regression model controlling for age, sex and education, global synaptic density was a significant predictor of performance on an extensive neuropsychological test battery. Synaptic density was particularly correlated with processing speed and visuospatial ability, but not verbal memory, possibly because of floor effects on the cognitive measures used to measure verbal memory.

The PSD-95 protein is the main presynaptic component of most AMPAR-containing synapses and plays an essential role in determining the ratio of AMPA to N-methyl-D-aspartate (NMDA) excitatory postsynaptic currents. PSD-95 also binds spectrin, an actin-binding protein that provides additional structural stability to the dendritic spines of excitatory neurons.

4. Synaptic Density Leads to Better Decision Making

Since Peter Huttenlocher painstakingly counted synapses in electron micrographs of postmortem brains, neuroscientists have known that synaptic density changes across the lifespan. In fact, it has been shown to increase rapidly shortly after birth, peak in adolescence, and then decline through adulthood, although there may be some compensatory changes late in life.

The postsynaptic density (PSD) is a dense protein complex first named by electron microscopists who found that it contains specialized scaffold proteins that physically link NMDARs and AMPARs to signaling cascades. The PSD also binds spectrin, which is an actin-binding protein that anchors the synapse to the cytoskeleton. The dynamics of this complex protein network are important to understanding synapse function and plasticity.

We used [11C]UCB-J PET and a comprehensive battery of neuropsychological tests to examine the relationship between cognitive performance and synaptic density in CN and AD participants. Global PSD-DVR was a significant predictor of performance on the global cognition measure, and regional PSD-DVR was also significantly associated with language, executive function, processing speed, and visuospatial ability.

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