Activation of D1/D5 receptors ameliorates decreased intrinsic excitability of hippocampal neurons induced by neonatal blockade of N‐methyl‐d‐aspartate receptors. (4th January 2022)

• Record Type: Journal Article
• Authors: Griego, Ernesto; Hernández‐Frausto, Melissa; Márquez, Luis A.; Lara‐Valderrabano, Leonardo; López Rubalcava, Carolina; Galván, Emilio J.
• Other Names: Camarini Rosana guestEditor.; Scavone Cristoforo guestEditor.; Berwick Daniel guestEditor.; Bailey Alexis guestEditor.
• Is Part Of: British journal of pharmacology. Volume 179:Number 8(2022)
• Page Start: 1695
• Page End: 1715
• Publication Date: 2022-01-04
• Subjects: CA1 pyramidal cells -- hippocampus -- intrinsic excitability -- MK‐801 -- potassium currents; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.15735
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : Background and Purpose: Dysregulation of dopaminergic transmission combined with transient hypofunction of N ‐methyl‐d ‐aspartate receptors (NMDARs) is a key mechanism that may underlie cognitive symptoms of schizophrenia. Experimental Approach: Therefore, we aimed to identify electrophysiologic alterations in animals neonatally treated with the NMDA receptor antagonist, MK‐801, or with saline solution. Key Results: Patch‐clamp whole‐cell recordings from MK‐801‐treated animals revealed altered passive and active electrophysiologic properties compared with CA1 pyramidal cells from saline‐treated animals, including up‐regulation of the K + inward‐rectifier conductance and fast‐inactivating and slow/non‐inactivating K + currents. Up‐regulation of these membrane ionic currents reduced the overall excitability and altered the firing properties of CA1 pyramidal cells. We also explored the capability of cells treated with MK‐801 to express intrinsic excitability potentiation, a non‐synaptic form of hippocampal plasticity associated with cognition and memory formation. CA1 pyramidal cells from animals treated with MK‐801 were unable to convey intrinsic excitability potentiation and had blunted synaptic potentiation. Furthermore, MK‐801‐treated animals also exhibited reduced cognitive performance in the Barnes maze task. Notably, activation of D1/D5 receptors with SKF‐38, 393 partially restored electrophysiologic alterations caused by neonatal treatment with MK‐801. Conclusion and Implications: Our results offer a molecular and mechanistic explanation based on dysregulation of glutamatergic transmission, in addition to dopaminergic transmission, that may contribute to the understanding of the cognitive deterioration associated with schizophrenia.