Impaired Fear Memory Specificity Associated with Deficient Endocannabinoid-Dependent Long-Term Plasticity

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2014-06, Vol.39 (7), p.1685-1693
• Main Authors: LOVELACE, Jonathan W, VIEIRA, Philip A, CORCHES, Alex, MACKIE, Ken, KORZUS, Edward
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Amino Acids - pharmacology; Animals; Animals, Newborn; Biological and medical sciences; Brain - pathology; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Conditioning (Psychology) - drug effects; Disease Models, Animal; Endocannabinoids - deficiency; Enzyme Inhibitors - pharmacology; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - toxicity; Fear - drug effects; Fear - physiology; Female; Long-Term Potentiation - drug effects; Long-Term Potentiation - physiology; Long-Term Synaptic Depression - drug effects; Long-Term Synaptic Depression - physiology; Male; Medical sciences; Memory; Memory Disorders - chemically induced; Memory Disorders - metabolism; Mice; Mice, Inbred C57BL; Neurons - drug effects; Neurosciences; Original; Phencyclidine - toxicity; Physiology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Psychosis; Receptors, N-Methyl-D-Aspartate - deficiency; Schizophrenia; Signal Transduction - drug effects; Software
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2014.15

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.