Impaired adrenergic-mediated plasticity of prefrontal cortical glutamate synapses in rats with developmental disruption of the ventral hippocampus.

TitleImpaired adrenergic-mediated plasticity of prefrontal cortical glutamate synapses in rats with developmental disruption of the ventral hippocampus.
Publication TypeJournal Article
Year of Publication2014
AuthorsBhardwaj SK, Tse YChung, Ryan R, Wong TPan, Srivastava LK
Date Published2014 Dec
KeywordsAdrenergic alpha-Antagonists, Animals, Animals, Newborn, Conditioning (Psychology), Developmental Disabilities, Excitatory Amino Acid Agonists, Excitatory Postsynaptic Potentials, Extinction, Psychological, Female, Glutamic Acid, Hippocampus, Ibotenic Acid, In Vitro Techniques, Male, Mitogen-Activated Protein Kinase 3, Neuronal Plasticity, Oxathiins, Prefrontal Cortex, Pregnancy, Rats, Receptors, Adrenergic, alpha-1, Synapses

Neonatal ventral hippocampus (nVH) lesion in rats is a useful model to study developmental origins of adult cognitive deficits and certain features of schizophrenia. nVH lesion-induced reorganization of excitatory and inhibitory neurotransmissions within prefrontal cortical (PFC) circuits is widely believed to be responsible for many of the behavioral abnormalities in these animals. Here we provide evidence that development of an aberrant medial PFC (mPFC) α-1 adrenergic receptor (α-1AR) function following neonatal lesion markedly affects glutamatergic synaptic plasticity within PFC microcircuits and contributes to PFC-related behavior abnormalities. Using whole-cell patch-clamp recording, we report that norepinephrine-induced α-1AR-dependent long-term depression (LTD) in a subset of cortico-cortical glutamatergic inputs is strikingly diminished in mPFC slices from nVH-lesioned rats. The LTD impairment occurs in conjunction with completely blunted α-1AR signaling through extracellular signal-regulated kinase 1/2. These α-1AR abnormalities have functional significance in a mPFC-related function, that is, extinction of conditioned fear memory. Post-pubertal animals with nVH lesion show significant resistance to extinction of fear by repeated presentations of the conditioned tone stimulus. mPFC infusion of an α-1AR antagonist (benoxathian) or LTD blocking peptide (Tat-GluR23Y) impaired fear extinction in sham controls, but had no significant effect in the lesioned animals. The data suggest that impaired α-1 adrenergic regulation of cortical glutamatergic synaptic plasticity may be an important mechanism in cognitive dysfunctions reported in neurodevelopmental psychiatric disorders.

Alternate JournalNeuropsychopharmacology
PubMed ID24917197
PubMed Central IDPMC4229566
Grant List68922-2 / / Canadian Institutes of Health Research / Canada
MOP-68922 / / Canadian Institutes of Health Research / Canada