NMDA receptor activity during postnatal development determines intrinsic excitability and mossy fiber long‐term potentiation of CA3 pyramidal cells

Experimental manipulations that interfere with the functional expression of N‐methyl‐D‐aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs...

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Veröffentlicht in:Hippocampus 2023-08, Vol.33 (8), p.906-921
Hauptverfasser: Márquez, Luis A., Griego, Ernesto, López Rubalcava, Carolina, Galván, Emilio J.
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Sprache:eng
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Zusammenfassung:Experimental manipulations that interfere with the functional expression of N‐methyl‐D‐aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK‐801 during early postnatal development alters glutamate release and impairs the induction of NMDAR‐dependent long‐term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR)‐mediated short‐ and long‐term potentiation, are compromised in response to neonatal treatment with MK‐801. Consistent with this tenet, short‐ and long‐term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole‐cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre‐ and postsynaptic modifications at the MF—CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired‐pulse ratio, and reduced AMPAR‐mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK‐801‐treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR‐independent forms of synaptic plasticity of the hippocampus.
ISSN:1050-9631
1098-1063
DOI:10.1002/hipo.23524