Aberrant hippocampal Atp8a1 levels are associated with altered synaptic strength, electrical activity, and autistic-like behavior.
Type IV ATPases are putative aminophospholipid translocases (APLTs), more commonly known as flippases. A pronounced induction of the flippase Atp8a1 was observed in post-mortem tissue homogenates from the hippocampus and temporal lobe of juvenile autistic subjects compared to age-matched controls. In order to simulate the human data, C57BL/6 mice were allowed to develop after intra-hippocampal injection of recombinant lentivirus expressing Atp8a1 at the early developmental stage of postnatal day 6 (P6). Transmission electron microscopy (TEM) analysis of the lentivirus-Atp8a1 treated (Atp8a1+) mice in adulthood revealed fewer and weaker excitatory synapses in the hippocampal CA1 region compared to mice injected with empty virus. Significant inhibition of the Schaffer collateral pathway was observed in the Atp8a1+ mice in paired-pulse recording (PPR) at 20-ms inter-stimulus interval. In the three-chambered sociability test, the Atp8a1+ mice displayed no preference for an encaged stranger mouse over a novel object, which is a characteristic autistic-like behavior. In sharp contrast, Atp8a1 (-/-) mice displayed a preference for a stranger mouse over the novel object, which is characteristic of neurotypical mouse behavior. However, similar to the Atp8a1+ mice, the Atp8a1 (-/-) mice harbored fewer and weaker excitatory synapses in CA1 compared to wild-type controls, and displayed inhibition at 20-ms inter-stimulus interval in PPR. These findings suggest that both elevated and diminished levels of Atp8a1 during early development are detrimental to brain connectivity, but only elevated Atp8a1 is associated with aberrant social behavior. Mice with augmented levels of Atp8a1 may therefore serve as a potential model in autism research.
Doctoral Program in Biology (CUNY), The College of Staten Island (CUNY), Staten Island, NY 10314, United States.
Daniel J
DJ
Kerr
Doctoral Program in Biology (CUNY), The College of Staten Island (CUNY), Staten Island, NY 10314, United States.
Alexandra
A
Marsillo
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, United States.
Sara R
SR
Guariglia
Doctoral Program in Biology (CUNY), The College of Staten Island (CUNY), Staten Island, NY 10314, United States.
Tatyana
T
Budylin
Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314, United States.
Rodina
R
Sadek
Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314, United States.
Silvia
S
Menkes
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, United States.
Abha
A
Chauhan
Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314, United States; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, United States.
Guang Y
GY
Wen
Doctoral Program in Psychology, CUNY Graduate Center, New York, NY 10016, United States; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314, United States.
Daniel P
DP
McCloskey
Department of Biology, The College of Staten Island (CUNY), Staten Island, NY 10314, United States; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314, United States.
Andrzej
A
Wieraszko
Doctoral Program in Biology (CUNY), The College of Staten Island (CUNY), Staten Island, NY 10314, United States; Department of Chemistry, The College of Staten Island (CUNY), Staten Island, NY 10314, United States; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314, United States. Electronic address: probal.banerjee@csi.cuny.edu.
Probal
P
Banerjee
D000251:Adenosine Triphosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism* / Q000523:psychology*; D001522:Behavior, Animal; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000648:ultrastructure; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D049294:Phospholipid Transfer Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012919:Social Behavior; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D013702:Temporal Lobe / Q000378:metabolism
D049294:Phospholipid Transfer Proteins; C580722:ATP8A1 protein, human; D000251:Adenosine Triphosphatases; C510547:Atp8a1 protein, mouse
Atp8a1; Autism; Flippase; Lenti-virus; Synaptic strength; TEM