Decreased synaptic vesicle recycling efficiency and cognitive deficits in amphiphysin 1 knockout mice.
The function of the clathrin coat in synaptic vesicle endocytosis is assisted by a variety of accessory factors, among which amphiphysin (amphiphysin 1 and 2) is one of the best characterized. A putative endocytic function of amphiphysin was supported by dominant-negative interference studies. We have now generated amphiphysin 1 knockout mice and found that lack of amphiphysin 1 causes a parallel dramatic reduction of amphiphysin 2 selectively in brain. Cell-free assembly of endocytic protein scaffolds is defective in mutant brain extracts. Knockout mice exhibit defects in synaptic vesicle recycling that are unmasked by stimulation and suggest impairments at multiple stages of the cycle. These defects correlate with increased mortality due to rare irreversible seizures and with major learning deficits, suggesting a critical role of amphiphysin for higher brain functions.
Di Paolo
Gilbert
G
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Sankaranarayanan
Sethuraman
S
Wenk
Markus R
MR
Daniell
Laurie
L
Perucco
Ezio
E
Caldarone
Barbara J
BJ
Flavell
Richard
R
Picciotto
Marina R
MR
Ryan
Timothy A
TA
Cremona
Ottavio
O
De Camilli
Pietro
P
D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D003214:Conditioning, Classical; D004705:Endocytosis / Q000502:physiology*; D005456:Fluorescent Dyes / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D018782:Maze Learning; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010433:Pentylenetetrazole / Q000494:pharmacology; D020033:Protein Isoforms; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D015996:Survival Rate; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure
D002966:Clathrin; C073804:FM1 43; C086686:FM2 10; D005456:Fluorescent Dyes; D018756:GABA Antagonists; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; C075637:amphiphysin; D018698:Glutamic Acid; D010433:Pentylenetetrazole