Title:
Roles of astroglia and microglia in synapse and neural network remodeling

Junichi Nabekura
1, Division of Homeostatic Development, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan
2, Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Japan

Abstract:
Recent advance in imaging techniques, e.g. MRI and PET, allows us to visualize the alteration of brain activity in various pathological conditions, such as Alzheimer disease, brain stroke and chronic pain. However, due to their spatial/temporal  limitation, it is difficult to elucidate their underlying mechanisms at neuronal circuits’ level in vivo, e.g.  Here, we introduce two evidences of dynamics of neuronal structures in pathologic brains and the contribution of glia to their synapse remodeling with taking an advantage of two photon excitation of fluorescent probes.
1) Real time imaging with 2 photon microscopy revealed that resting microglia, the primary immune cells in the brain, dynamically and directly monitors the local synaptic states. In intact mature brain, resting microglial processes make a brief (～5 min) and direct contact with neuronal synapses. At the penumbra of the ischemic brain, microglia-synapse contact duration were prolonged (～1 hour), frequently followed by the disappearance of presynaptic boutons. In addition, the neuronal hyperactivity often induced axonal swelling and a sporadic pathological membrane depolarization. Microglial process approached to and wrapped the swollen axon by detecting ATP released though a volume-activated chloride channel of swollen axon. As a result, microglial contact repolarized the membrane potential to rescue the neurons from excitotoxicity.
2) Repeated observation of the same neuronal structures of the mouse cortex over several months reveals the dynamics of dendritic spines of somatosensory cortex in neuropathic pain. An increase of spine turnover in the S1 corresponding to the injured paw was limited during an early developing phase of neuropathic pain, in which preexisting stable spines preferentially eliminated. In this early phase, the activity of astrocyte in the S1 selectively enhanced. Activation of astrocyte could induce a release of thrombospondin, resulting in accelerating the spine turnover, which could the underlying mechanism of exaggerating the neuronal response in the somatosensory cortex to peripheral stimulation.