Dataset Information

Preferential pruning of inhibitory synapses by microglia contributes to alteration of the balance between excitatory and inhibitory synapses in the hippocampus in temporal lobe epilepsy.

ABSTRACT:

Background

A consensus has formed that neural circuits in the brain underlie the pathogenesis of temporal lobe epilepsy (TLE). In particular, the synaptic excitation/inhibition balance (E/I balance) has been implicated in shifting towards elevated excitation during the development of TLE.

Methods

Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to generate a model of TLE. Next, electroencephalography (EEG) recording was applied to verify the stability and detectability of spontaneous recurrent seizures (SRS) in rats. Moreover, hippocampal slices from rats and patients with mesial temporal lobe epilepsy (mTLE) were assessed using immunofluorescence to determine the alterations of excitatory and inhibitory synapses and microglial phagocytosis.

Results

We found that KA induced stable SRSs 14 days after status epilepticus (SE) onset. Furthermore, we discovered a continuous increase in excitatory synapses during epileptogenesis, where the total area of vesicular glutamate transporter 1 (vGluT1) rose considerably in the stratum radiatum (SR) of cornu ammonis 1 (CA1), the stratum lucidum (SL) of CA3, and the polymorphic layer (PML) of the dentate gyrus (DG). In contrast, inhibitory synapses decreased significantly, with the total area of glutamate decarboxylase 65 (GAD65) in the SL and PML diminishing enormously. Moreover, microglia conducted active synaptic phagocytosis after the formation of SRSs, especially in the SL and PML. Finally, microglia preferentially pruned inhibitory synapses during recurrent seizures in both rat and human hippocampal slices, which contributed to the synaptic alteration in hippocampal subregions.

Conclusions

Our findings elaborately characterize the alteration of neural circuits and demonstrate the selectivity of synaptic phagocytosis mediated by microglia in TLE, which could strengthen the comprehension of the pathogenesis of TLE and inspire potential therapeutic targets for epilepsy treatment.

SUBMITTER: Fan J

PROVIDER: S-EPMC10493672 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Preferential pruning of inhibitory synapses by microglia contributes to alteration of the balance between excitatory and inhibitory synapses in the hippocampus in temporal lobe epilepsy.

Fan Jianchen J Dong Xinyan X Tang Yejiao Y Wang Xuehui X Lin Donghui D Gong Lifen L Chen Chen C Jiang Jie J Shen Weida W Xu Anyu A Zhang Xiangnan X Xie Yicheng Y Huang Xin X Zeng Linghui L

CNS neuroscience & therapeutics 20230418 10

<h4>Background</h4>A consensus has formed that neural circuits in the brain underlie the pathogenesis of temporal lobe epilepsy (TLE). In particular, the synaptic excitation/inhibition balance (E/I balance) has been implicated in shifting towards elevated excitation during the development of TLE.<h4>Methods</h4>Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to generate a model of TLE. Next, electroencephalography (EEG) recording was applied to verify the stability ...[more]

PMID: 37072932

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Project description:A key feature of excitatory synapses is the existence of subsynaptic protein nanoclusters whose precise alignment across the cleft in a trans-synaptic nanocolumn influences the strength of synaptic transmission. However, whether nanocolumn properties vary between excitatory synapses functioning in different cellular contexts is unknown. We used a combination of confocal and DNA-PAINT super-resolution microscopy to directly compare the organization of shared scaffold proteins at two important excitatory synapses - those forming onto excitatory principal neurons (Ex→Ex synapses) and those forming onto parvalbumin-expressing interneurons (Ex→PV synapses). As in Ex→Ex synapses, we find that in Ex→PV synapses presynaptic Munc13-1 and postsynaptic PSD-95 both form nanoclusters that demonstrate alignment, underscoring synaptic nanostructure and the trans-synaptic nanocolumn as conserved organizational principles of excitatory synapses. Despite the general conservation of these features, we observed specific differences in the characteristics of pre- and postsynaptic Ex→PV nanostructure. Ex→PV synapses contained larger PSDs with fewer PSD-95 NCs when accounting for size than Ex→Ex synapses. Furthermore, the PSD-95 NCs were larger and denser. The identity of the postsynaptic cell also had a retrograde impact on Munc13-1 organization, as Ex→PV synapses hosted larger Munc13-1 puncta that contained less dense but larger and more numerous Munc13-1 NCs. Moreover, we measured the spatial variability of transsynaptic alignment in these synapse types, revealing protein alignment in Ex→PV synapses over a distinct range of distances compared to Ex→Ex synapses. We conclude that while general principles of nanostructure and alignment are shared, cell-specific elements of nanodomain organization likely contribute to functional diversity of excitatory synapses. Understanding the rules of synapse nanodomain assembly, which themselves are cell-type specific, will be essential for illuminating brain network dynamics.

Dataset Information

Preferential pruning of inhibitory synapses by microglia contributes to alteration of the balance between excitatory and inhibitory synapses in the hippocampus in temporal lobe epilepsy.

Background

Methods

Results

Conclusions

Publications

Preferential pruning of inhibitory synapses by microglia contributes to alteration of the balance between excitatory and inhibitory synapses in the hippocampus in temporal lobe epilepsy.

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