How to make brain more socialized? Microglia needed
(by Haohao Wu, )

As gardeners prune the bush to get fruits, in the early postnatal development of mammalian brains, weak or unwanted synapses are pruned by the gardener in the brain, microglia, leaving more efficient synaptic configurations. A recent study by Cornelius Gross and colleagues from European Molecular Biology Laboratory (EMBL) shows that deficits in microglia can induce deficits in functional connectivity in mouse brains and consequently resulted in some autism-related behaviors.

In this study, researchers used knockout mice which lack of chemokine receptor Cx3cr1. These mice had a transient reduction of microglia in the brain in early postnatal weeks, thus failed to eliminate immature synapses during this significant window. The researchers found this transient reduction of microglia in turn had a long-term effect on the synaptic multiplicity (number of synapses per one axonal input), meaning that microglia-mediated synaptic pruning is essential for circuit maturation.

Logically, the decreased synaptic multiplicity may suggest a reduced connectivity between different brain regions. To quantify long-range functional connectivity, the researchers further measured coherence of local field potentials (LFPs). And to assess global functional connectivity, the researchers quantified the synchronization of blood oxygen level-dependent (BOLD) fMRI signals across brain regions. Results showed that along with the deficits in synaptic multiplicity, the long-range and global functional connectivity in the brains of knockout mice were deficient.

This is a process of information encodingin the brain.

Fig. 1: Decreased functional connectivity in knockout mice. The upper images show correlation matrices from global fMRI BOLD signal analysis, indicating reduction of functional connectivity across brain regions in knockout mice compared with wild-type mice. The lower images show the most prominent fMRI BOLD correlations between brain regions in WT and KO mice.
(Picture modified from Zhan Yang et al./ Nature neuroscience)

Previously, reduced functional connectivity was reported to be linked with autism and other neurodevelopmental disorders. The researchers in this study then explored the social behavior of Cx3cr1 knockout mice and found that these mice showed a decreased social interaction and increased repetitive behavior. These two behaviors are typical behaviors for patients of autism, obsessive-compulsive disorder and other neurodevelopmental disorders.

Based on all these observations, a primary deficits in microglia seems to be sufficient to cause decreased long-range functional connectivity, therefore should be a possible pathological mechanism in neurodevelopmental disorders which show weak functional connectivity, such as autism. However, in human, the neurodevelopmental and psychiatric disorders involve many genes together with environmental factors, thus, it maybe still too early to translate the result of this study, which is based on one single gene, to human.

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ZhanYang, Rosa C. Paolicelli, Francesco Sforazzini, LaetitiaWeinhard, Giulia Bolasco, Francesca Pagani, Alexei L. Vyssotski et al. "Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior." Nature neuroscience (2014).