Journal
JOURNAL OF NEUROSCIENCE
Volume 38, Issue 6, Pages 1493-1510Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1548-17.2017
Keywords
correlative light and electron microscopy; cryo-electron tomography; neurotransmitter receptor; postsynaptic density; synaptic ultrastructure; synaptic vesicle
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Funding
- Chinese Academy of Sciences [XDB02050000]
- National Natural Science Foundation of China [30725017, 91232722, 31070935]
- China Ministry of Science and Technology [2009CB941300]
- National Institutes of Health (NIH) [GM071940]
- NIH [S10RR23057, S10OD018111]
- National Science Foundation [DBI-133813]
- BBSRC [BB/S003339/1] Funding Source: UKRI
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As key functional units in neural circuits, different types of neuronal synapses play distinct roles in brain information processing, learning, and memory. Synaptic abnormalities are believed to underlie various neurological and psychiatric disorders. Here, by combining cryo-electron tomography and cryo-correlative light and electron microscopy, we distinguished intact excitatory and inhibitory synapses of cultured hippocampal neurons, and visualized the in situ 3D organization of synaptic organelles and macromolecules in their native state. Quantitative analyses of >100 synaptic tomograms reveal that excitatory synapses contain a mesh-like postsynaptic density (PSD) with thickness ranging from 20 to 50 nm. In contrast, the PSD in inhibitory synapses assumes a thin sheet-like structure similar to 12 nm from the postsynaptic membrane. On the presynaptic side, spherical synaptic vesicles (SVs) of 25-60 nm diameter and discus-shaped ellipsoidal SVs of various sizes coexist in both synaptic types, with more ellipsoidal ones in inhibitory synapses. High-resolution tomograms obtained using a Volta phase plate and electron filtering and counting reveal glutamate receptor-like and GABAA receptor-like structures that interact with putative scaffolding and adhesion molecules, reflecting details of receptor anchoring and PSD organization. These results provide an updated view of the ultrastructure of excitatory and inhibitory synapses, and demonstrate the potential of our approach to gain insight into the organizational principles of cellular architecture underlying distinct synaptic functions.
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