Orexins/hypocretins control bistability of hippocampal long-term synaptic plasticity through co-activation of multiple kinases.
OBJECTIVE
Orexins/hypocretins (OX/Hcrt) are hypothalamic neuropeptides linking sleep-wakefulness, appetite and neuroendocrine control. Their role and mechanisms of action on higher brain functions, such as learning and memory, are not clear.


METHODS
We used field recordings of excitatory post-synaptic potentials (fEPSP) in acute mouse brain slice preparations to study the effects of orexins and pharmacological inhibitors of multiple kinases on long-term synaptic plasticity in the hippocampus.


RESULTS
Orexin-A (OX-A) but not orexin-B (OX-B) induces a state-dependent long-term potentiation of synaptic transmission (LTP(OX)) at Schaffer collateral-CA1 synapses in hippocampal slices from adult (8- to 12-week-old) mice. In contrast, OX-A applied to slices from juvenile (3- to 4-week-old) animals causes a long-term depression (LTD(OX)) in the same pathway. LTP(OX) is blocked by pharmacological inhibition of orexin receptor-1 (OX1R) and plasticity-related kinases, including serine/threonine- (CaMKII, PKC, PKA, MAPK), lipid- (PI3K), and receptor tyrosine kinases (Trk). Inhibition of OX1R, CaMKII, PKC, PKA and Trk unmasks LTD(OX) in adult animals.


CONCLUSIONS
Orexins control not only the bistability of arousal states and threshold for appetitive behaviours but, in an age- and kinase-dependent manner, also bidirectional long-term synaptic plasticity in the hippocampus, providing a possible link between behavioural state and memory functions.
Selbach
O
O
Department of Neurophysiology, Heinrich-Heine-University, Dusseldorf, Germany. selbach@uni-duesseldorf.de
Bohla
C
C
Barbara
A
A
Doreulee
N
N
Eriksson
K S
KS
Sergeeva
O A
OA
Haas
H L
HL
D000375:Aging / Q000502:physiology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D000068797:Orexins; D010770:Phosphotransferases / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D000068797:Orexins; D010770:Phosphotransferases