Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome.
In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of an NS-associated allele PTPN11(D61G) in adult mouse hippocampus results in increased baseline excitatory synaptic function and deficits in LTP and spatial learning, which can be reversed by a mitogen-activated protein kinase kinase (MEK) inhibitor. Furthermore, brief treatment with lovastatin reduces activation of the GTPase Ras-extracellular signal-related kinase (Erk) pathway in the brain and normalizes deficits in LTP and learning in adult Ptpn11(D61G/+) mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS.
1] Integrative Center for Learning and Memory, Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, University of California Los Angeles, Los Angeles, California, USA. [2] Department of Life Science, Chung-Ang University, Seoul, Korea.
Yong-Seok
YS
Lee
Integrative Center for Learning and Memory, Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, University of California Los Angeles, Los Angeles, California, USA.
Dan
D
Ehninger
Integrative Center for Learning and Memory, Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, University of California Los Angeles, Los Angeles, California, USA.
Miou
M
Zhou
Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, Korea.
Jun-Young
JY
Oh
Department of Life Science, Chung-Ang University, Seoul, Korea.
Minkyung
M
Kang
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea.
Chuljung
C
Kwak
Department of Life Science, Chung-Ang University, Seoul, Korea.
Hyun-Hee
HH
Ryu
Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Delana
D
Butz
Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
Toshiyuki
T
Araki
Integrative Center for Learning and Memory, Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, University of California Los Angeles, Los Angeles, California, USA.
Ying
Y
Cai
Integrative Center for Learning and Memory, Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, University of California Los Angeles, Los Angeles, California, USA.
J
J
Balaji
Integrative Center for Learning and Memory, Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, University of California Los Angeles, Los Angeles, California, USA.
Yoshitake
Y
Sano
Integrative Center for Learning and Memory, Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, University of California Los Angeles, Los Angeles, California, USA.
Christine I
CI
Nam
Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, Korea.
Hyong Kyu
HK
Kim
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea.
Bong-Kiun
BK
Kaang
Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Corinna
C
Burger
Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
Benjamin G
BG
Neel
Integrative Center for Learning and Memory, Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, University of California Los Angeles, Los Angeles, California, USA.
Alcino J
AJ
Silva
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009634:Noonan Syndrome / Q000188:drug therapy / Q000503:physiopathology*; D011897:Random Allocation; D051381:Rats; D016896:Treatment Outcome
D008148:Lovastatin