Aberrant hippocampal Atp8a1 levels are associated with altered synaptic strength, electrical activity, and autistic-like behavior

• Published in: Biochimica et biophysica acta Vol. 1862; no. 9; pp. 1755 - 1765
• Main Authors: Kerr, Daniel J., Marsillo, Alexandra, Guariglia, Sara R., Budylin, Tatyana, Sadek, Rodina, Menkes, Silvia, Chauhan, Abha, Wen, Guang Y., McCloskey, Daniel P., Wieraszko, Andrzej, Banerjee, Probal
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-09-2016
• Subjects: Adenosine Triphosphatases - deficiency; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Animals; Atp8a1; Autism; Autistic Disorder - genetics; Autistic Disorder - metabolism; Autistic Disorder - psychology; Behavior, Animal; CA1 Region, Hippocampal - metabolism; CA1 Region, Hippocampal - ultrastructure; Case-Control Studies; Child; Child, Preschool; Disease Models, Animal; Flippase; Hippocampus - metabolism; Humans; Lenti-virus; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Phospholipid Transfer Proteins - deficiency; Phospholipid Transfer Proteins - genetics; Phospholipid Transfer Proteins - metabolism; Social Behavior; Synapses - metabolism; Synapses - ultrastructure; Synaptic strength; TEM; Temporal Lobe - metabolism; Autism; Atp8a1; Synaptic strength; TEM; Lenti-virus; Flippase
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2016.06.005

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.
•IIncreased Atp8a1 expression in the hippocampus and temporal cortex of juvenile patients with autism.•Lentiviral – transduced Atp8a1 overexpression at p6 elicits autistic-like sociability behavior in adult mice•Mice deficient in Atp8a1 display normal sociability behavior.•Altered expression of Atp8a1 yield mice that display decreased excitatory synapses in the hippocampal CA1 region•The Atp8a1+ mice may serve as an animal model for autism.