A critical period for nicotine-induced disruption of synaptic development in rat auditory cortex.
Cholinergic markers in the middle layers of rat auditory cortex are transiently upregulated during the second postnatal week, at which time alpha 7 nicotinic acetylcholine receptors (nAChRs) selectively regulate NMDA receptor (NMDAR)-mediated EPSPs. To investigate the developmental role of this regulation, we determined whether manipulating nAChR function at specific times during the first 4 weeks after birth could alter subsequent neuronal function. Rat pups were injected twice daily with nicotine (1 or 2 mg/kg) or saline during approximately the first, second, or fourth postnatal week (i. e., before, during, or after the peak upregulation of nAChRs). Glutamate EPSPs and intrinsic membrane properties were measured during whole-cell recordings from visually identified pyramidal neurons in layers II-IV of brain slices prepared at least 15 hr after the last injection. Chronic nicotine exposure (CNE) had little effect on intrinsic membrane properties and during week 1 or 4 did not affect synaptic function. However, CNE during week 2 resulted in EPSPs with long durations, multiple peaks, and enhanced NMDAR components. These changes remained significant even 10 d after CNE. Rapid application of nicotine, which in control neurons selectively enhances NMDAR EPSPs during week 2, produced only weak effects after CNE. Receptor binding studies showed that CNE-induced EPSP alterations occurred in the absence of altered alpha 7 nAChR numbers or agonist binding affinity. Thus, altered stimulation of nAChRs by CNE during week 2, but not before or after, disrupts the development of glutamate synapses in rat auditory cortex.
Aramakis
V B
VB
Departments of Neurobiology and Behavior, University of California, Irvine, California 92697-4550, USA.
Hsieh
C Y
CY
Leslie
F M
FM
Metherate
R
R
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001303:Auditory Cortex / Q000187:drug effects* / Q000254:growth & development* / Q000503:physiopathology; D004334:Drug Administration Schedule; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008845:Microinjections; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009538:Nicotine / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579165:Chrna7 protein, rat; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine