D1-like receptor activation rescues hippocampal synaptic plasticity and cognitive impairments in the MK-801 schizophrenia model.

Abstract

Schizophrenia is a disorder with a higher cognitive decline in early adulthood, causing impaired retention of episodic memories. However, the physiological and behavioral functions that underlie cognitive deficits with a potential mechanism to ameliorate and improve cognitive performance are unknown. In this study, we used the MK-801 neurodevelopmental schizophrenia-like model. Rats were divided into two groups: one received MK-801, and the other received saline for five consecutive days (7-11 postnatal days, PND). Using extracellular field recordings in acute hippocampal slices and the Barnes maze task, we evaluated synaptic plasticity late-LTP and spatial memory in freely moving animals in early adolescence and young adulthood. Next, we examined D1-like activation as a mechanism to ameliorate cognitive impairments. Our results suggest that MK-801 neonatal treatment induces impairment in late-LTP expression and deficits in spatial memory retrieval in early adolescence that is maintained until young adulthood. Furthermore, we found that activation of D1-like dopamine receptors ameliorates the impairments and promotes a robust expression of late-LTP and an improved performance in the Barnes maze task, suggesting a novel and potential therapeutic role in treating cognitive impairments in schizophrenia. Highlights- MK-801 Schizophrenia model induces impairment in Late-LTP at early adolescence and young developmental stage. - Barnes maze recall phase is impaired in the MK-801 Schizophrenia model. - The activation of D1-like receptors promotes recovery and induction of the - Late-LTP in the MK-801 schizophrenia model in adolescent and young adult rats. - Activation of D1-like dopamine receptors improves behavioral performance in the MK-801 schizophrenia model in adolescent and young adult rats. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/599791v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@e258e7org.highwire.dtl.DTLVardef@3ab481org.highwire.dtl.DTLVardef@20aa4dorg.highwire.dtl.DTLVardef@8cc518_HPS_FORMAT_FIGEXP M_FIG C_FIG Disturbances in episodic memories are observed in patients with schizophrenia and rodent models. Still, the hippocampal physiological substrates with a potential rescue mechanism related to consolidation of memories have not been elucidated. Here, in vitro electrophysiology and in vivo Barnes maze task are used at two ages in the MK-801 neurodevelopmental schizophrenia-like model. We observed a loss of hippocampal late-LTP and impaired recall phase, and the activation of dopamine D1-like receptors attenuated the impairments with a rescue of both late-LTP and recall phase, suggesting an important role of D1-like receptors activity for episodic memory in schizophrenia.