GluN2B-containing NMDA receptors and AMPA receptors in medial prefrontal cortex are necessary for odor span in rats.

Don A Davies,John G Howland,Quentin Greba

doi:10.3389/fnbeh.2013.00183

Abstract

Working memory is a type of short-term memory involved in the maintenance and manipulation of information essential for complex cognition. While memory span capacity has been extensively studied in humans as a measure of working memory, it has received considerably less attention in rodents. Our aim was to examine the role of the N-methyl-D-aspartate (NMDA) and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in odor span capacity using systemic injections or infusions of receptor antagonists into the medial prefrontal cortex (mPFC). Long Evans rats were trained on a well-characterized odor span task (OST). Initially, rats were trained to dig for a food reward in sand followed by training on a non-match to sample discrimination using sand scented with household spices. The rats were then required to perform a serial delayed non-match to sample procedure which was their odor span. Systemic injection of the broad spectrum NMDA receptor antagonist 3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) (10 mg/kg) or the GluN2B-selective antagonist Ro 25-6981 (10 mg/kg but not 6 mg/kg) significantly reduced odor span capacity. Infusions of the GluN2B- selective antagonist Ro 25-6981 (2.5 μg/hemisphere) into mPFC reduced span capacity, an effect that was nearly significant (p = 0.069). Infusions of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (1.25 μg/hemisphere) into mPFC reduced span capacity and latency for the rats to make a choice in the task. These results demonstrate span capacity in rats depends on ionotropic glutamate receptor activation in the mPFC. Further understanding of the circuitry underlying span capacity may aid in the novel therapeutic drug development for persons with working memory impairments as a result of disorders such as schizophrenia and Alzheimer’s disease.

Highlights

Working memory, a type of short term memory, enables the maintenance and manipulation of information needed for complex cognitive functions (Goldman-Rakic, 1996; Baddeley, 2003; D’Esposito, 2007)
The present study revealed a series of novel findings: (1) span capacity of untreated rats significantly increased from a mean of approximately 7 to a mean of approximately 13 following the www.frontiersin.org first treatment (Figure 1C); (2) systemic injections of the broad spectrum NMDA receptor antagonist CPP significantly reduced span capacity (Figure 2A); (3) systemically administered Ro 256981 dose-dependently impaired odor span (Figures 2C, E); (4) GluN2B subunit-containing NMDA receptors in the medial prefrontal cortex (mPFC) may be involved in performance of the odor span task (OST) because Ro 256981 infusions into the mPFC marginally impaired span capacity (Figure 3A); (5) blocking Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in mPFC with CNQX
PERFORMANCE OF RATS ON THE ODOR SPAN TASK Rats in the present experiment initially performed to those reported in a previous publication from our group (Davies et al, 2013) and others using the version of the OST that requires the rats to dig in scented sand (Rushforth et al, 2010, 2011)

Summary

Introduction

A type of short term memory, enables the maintenance and manipulation of information needed for complex cognitive functions (Goldman-Rakic, 1996; Baddeley, 2003; D’Esposito, 2007). Working memory capacity has been studied in rodents using span tasks with odors or spatial locations as stimuli. One of these tasks is the odor span task (OST) first developed by Dudchenko et al (2000) (Figure 1A). The OST is an incremental non-match-to-sample task where rats or mice receive a food reward by choosing to dig in a bowl of sand with the novel scent (Dudchenko et al, 2000; Young et al, 2007; Rushforth et al, 2010, 2011; Davies et al, 2013) or by moving scented lids (MacQueen et al, 2011; April et al, 2013; Galizio et al, 2013). Span capacity declines following reversible inactivation of the medial prefrontal

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