Impaired fear memory specificity associated with deficient endocannabinoid-dependent long-term plasticity.
In addition to its central role in learning and memory, N-methyl D-aspartate receptor (NMDAR)-dependent signaling regulates central glutamatergic synapse maturation and has been implicated in schizophrenia. We have transiently induced NMDAR hypofunction in infant mice during postnatal days 7-11, followed by testing fear memory specificity and presynaptic plasticity in the prefrontal cortex (PFC) in adult mice. We show that transient NMDAR hypofunction during early brain development, coinciding with the maturation of cortical plasticity results in a loss of an endocannabinoid (eCB)-mediated form of long-term depression (eCB-LTD) at adult central glutamatergic synapses, while another form of presynaptic long-term depression mediated by the metabotropic glutamate receptor 2/3 (mGluR2/3-LTD) remains intact. Mice with this selective impairment of presynaptic plasticity also showed deficits in fear memory specificity. The observed deficit in cortical presynaptic plasticity may represent a neural maladaptation contributing to network instability and abnormal cognitive functioning.
Department of Psychology and Neuroscience Program, University of California, Riverside, CA, USA.
Jonathan W
JW
Lovelace
Department of Psychology and Neuroscience Program, University of California, Riverside, CA, USA.
Philip A
PA
Vieira
Biomedical Sciences Program, University of California, Riverside, CA, USA.
Alex
A
Corches
Department of Psychological and Brain Sciences, Gill Center for Biomedical Sciences, Indiana University, Bloomington, IN, USA.
Ken
K
Mackie
1] Department of Psychology and Neuroscience Program, University of California, Riverside, CA, USA [2] Biomedical Sciences Program, University of California, Riverside, CA, USA.
Edward
E
Korzus
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000172:deficiency*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005260:Female; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D010622:Phencyclidine / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C118218:LY 379268; D016194:Receptors, N-Methyl-D-Aspartate; D010622:Phencyclidine