Enhanced synaptic connectivity and epilepsy in C1q knockout mice
Open accessAbstract
Excessive CNS synapses are eliminated during development to establish mature patterns of neuronal connectivity. A complement cascade protein, C1q, is involved in this process. Mice deficient in C1q fail to refine retinogeniculate connections resulting in excessive retinal innervation of lateral geniculate neurons. We hypothesized that C1q knockout (KO) mice would exhibit defects in neocortical synapse elimination resulting in enhanced excitatory synaptic connectivity and epileptiform activity. We recorded spontaneous and evoked field potential activity in neocortical slices and obtained video-EEG recordings from implanted C1q KO and wild-type (WT) mice. We also used laser scanning photostimulation of caged glutamate and whole cell recordings to map excitatory and inhibitory synaptic connectivity. Spontaneous and evoked epileptiform field potentials occurred at multiple sites in neocortical slices from C1q KO, but not WT mice. Laser mapping experiments in C1q KO slices showed that the proportion of glutamate uncaging sites from which excitatory postsynaptic currents (EPSCs) could be evoked (“hotspot ratio”) increased significantly in layer IV and layer V, although EPSC amplitudes were unaltered. Density of axonal boutons was significantly increased in layer V pyramidal neurons of C1q KO mice. Implanted KO mice had frequent behavioral seizures consisting of behavioral arrest associated with bihemispheric spikes and slow wave activity lasting from 5 to 30 s. Results indicate that epileptogenesis in C1q KO mice is related to a genetically determined failure to prune excessive excitatory synapses during development.
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Deficits in complement component C1q result in an increase in the number of presynaptic boutons and exuberant excitatory connectivity in the cortex.
“Consistent with this idea, deficits in complement component C1q results in an increase in the number of presynaptic boutons and exuberant excitatory connectivity in the cortex (Chu et al., 2010).”
From Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner (2012) · cites this paper as Chu et al., 2010
KO mice lacking complement factors show cortical excitatory hyperconnectivity, supporting a role for microglia in elimination of excess synapses in mammalian neocortex.
“Knockout (KO) mice lacking complement factors show cortical excitatory hyperconnectivity10, supporting a role for microglia in the elimination of excess synapses in the mammalian neocortex.”
From Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction (2018) · cites this paper as [10]
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- Authors
- Chu, Y., Jin, X., Parada, I., Pesic, A., Stevens, B., Barres, B., & Prince, D. A.
- Affiliations
- Stanford Medicine (US)
- Departments of Neurology and Neurological Sciences and
- Stanford University (US)
- Harvard University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-04-07
- Volume
- 107
- Issue
- 17
- Pages
- 7975-7980
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2867906
- OpenAlex
- W2092935640
- Cited by
- 364
- References
- 33
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 16 · 2023: 29 · 2022: 20 · 2021: 45 · 2020: 31 · 2019: 24 · 2018: 33 · 2017: 29 · 2016: 13 · 2015: 16 · 2014: 19 · 2013: 18 · 2012: 19
- FWCI
- 12.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS039579, P01NS012151, K99NS057940, P50NS012151, NS12151)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- C1q, complement system, synaptic pruning, epileptogenesis, epilepsy, neocortex, excitatory postsynaptic currents, axonal boutons, pyramidal neurons, behavioral seizures, field potentials, layer 4, layer V
- MeSH terms
- Analysis of Variance, Animals, Electroencephalography, Epilepsy, Evoked Potentials, Glutamates, Mice, Inbred C57BL, Photic Stimulation, Synapses, Complement C1q, Mice, Knockout, Patch-Clamp Techniques, Microscopy, Video, Neocortex, Mice
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