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Section CELLULAR NEUROSCIENCE
Structural Plasticity of Synaptic Environment: a Quest into the Machinery
D.A. Rusakov u *
1 UCL Institute of Neurology, University College London, United Kingdom;
2 Laboratory of Brain Microcircuits, Nizhny Novgorod University, Russia.
* Presenting e-mail: d.rusakov@ucl.ac.uk
Memory formation in the human brain is thought to rely on the structural remodelling of synaptic connections which ultimately leads to the 'rewiring' of neural circuitry. This process is likely to involve thin astroglial pro-trusions occurring in the immediate vicinity of excitatory synapses. Indeed, recent evidence has associated astroglial Ca2+ activity with diverse molecular signals that can affect the efficacy or functional modality of synaptic connections. The phenomenology, cellular mechanisms and the causal relationships of usedependent astroglial restructuring remain however poorly understood. To monitor rapid rearrangement of astroglia on the nanoscale upon induction of long-term potentiation (LTP, an established experimental model of synaptic memory), we combined electrophysiology with two-photon excitation microscopy and photolytic uncaging.
We document NMDA receptor dependent-withdrawal of astroglial processes from the immediate proximity of synapses following LTP induction, both at the level of synaptic populations and at the level of individual potentiated synapses. This reduction in synaptic astroglial coverage facilitates escape of glutamate discharged into the synaptic cleft, thus boosting cross-talk among extrasynaptic NMDA receptors that might well represent neighboring cells. The molecular mechanisms behind astroglial restructuring are accompanied by local Ca2+ elevations but do not appear to involve mGluRs or IP3-receptor dependent Ca2+ signalling. They however depend on the availability of aquaporin AQP4. Experiments are underway to build a conceptual understanding of the molecular interactions that act within the microscopic vicinity of synapses in the course of synaptic plasticity.
Effects of Thyroid Hormones in Neuron-Glia Interaction
Mami Noda* and Yusaku Yoshioka
Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
* Presenting e-mail: noda@phar.kyushu-u.ac.jp
Aims
L-tri-iodothyronine (3, 3', 5-triiodothyronine; T3) is an active form of the thyroid hormone (TH) essential for the development and function of the central nervous system (CNS). Circulating thyroxine (T4) crosses blood-brain barrier via specific transporters. T4 in the brain is taken up by astrocytes, de-iodinated to produce T3, and then taken by other cells (Fig. 1). In adult CNS, both hypo- and hyper-thyroidism may affect psychological condition and potentially increase the risk of cognitive impairment and neurodegeneration including Alzheimer's disease (AD). We have reported non-genomic effects of T3 on microglial functions and its signaling in vitro (Mori et al., GLIA, 2015). To investigate whether or not different THs level affects glial cells and neurons in vivo, the effects of hyper- and hypothyroidism on microglia, astrocytes and dendritic spines were investigated.
Methods
Hyper- or hypothyroidism was induced by intraperitoneally injecting T4 (0.3 mg/kg) 4 times during 2 weeks or propylth-iouracyl (60 mg/kg/day) for 21 days. The morphological changes in microglia and astrocytes in the cerebral cortex and hippocampus in C57/BL6 mice were investigated by immunohistochemical analysis. The dendritic spines were analyzed by electron microscopy. Behavioral changes in young male mice under hyperthyroidism were investigated using open field test and tail suspension test.
Results
Both microglia and astrocytes were morphologically activated with abnormal level of THs. Interestingly, effects of hyperand hypothyroidism on glial cells were sex- and age-dependent; Only in young male mice, morphologically activated glial cells were observed. With hypothyroidism, activation of glial cells was observed in young female mice, while in old
OM&P
Section CELLULAR NEUROSCIENCE
OM&P
female mice glial cells showed rather inhibited morphology. In young male mice with hyperthyroidism, increase in general locomotor activity and willingness to explore was observed, while there was no significant change in tail suspension test, one of the most widely used models for assessing antidepressant-like activity in mice.
Fig. 1. Transport of THs to the brain and their metabolism. Conclusion
THs are transported into the brain, metabolized in astrocytes and affect microglia and oligodendrocytes, demonstrating an example of glioendocrine system. Dysfunction of THs may impair glial function and thus disturb the brain function. Our results may help to understand physiological and/or pathophysiological functions of THs in the CNS and how hypo- and hyper-thyroidism may cause neurological disorders and their age- and sex-dependence.
Acknowledgements
We thank Prof. Akinori Nishi and Dr. Yosuke Kitahara (Kurume University, Japan) and Kyushu University Support Center for their experimental help.
References
1. Y. Mori, D. Tomonaga, A. Kalashnikova, F. Furuya, N. Akimoto, M. Ifuku, Y. Okuno, K. Beppu, K. Fujita, T. Katafuchi, H. Shimura, L.P. Churilov, M. Noda. Glia., 2015, 63, 906-920.
2. M. Noda. Front. Cell. Neurosci., 2015, Jun 3;9:194.doi: 10.3389/fncel.2015.00194.
Linking AMPA Receptor Nanoscale Organization and Function at Excitatory Synapses
Daniel Choquet*
Institut Interdisciplinaire de Neuroscience, UMR 5297 CNRS-Université de Bordeaux. * Presenting e-mail: dchoquet@u-bordeaux2.fr
The spatio-temporal organization of neurotransmitter receptors in the postsynaptic membrane is a fundamental determinant of synaptic transmission and thus information processing by the brain. Ionotropic AMPA glutamate receptors (AMPAR) mediate fast excitatory synaptic transmission in the central nervous system. Using a combination of high resolution single molecule imaging techniques and video-microscopy, we had previously established that AMPARs are not stable in the synapse as thought initially, but undergo continuous entry and exit to and from the post-synaptic density through lateral diffusion.
