Maintenance of enriched environment-induced changes of auditory spatial sensitivity and expression of GABAA, NMDA, and AMPA receptor subunits in rat auditory cortex

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Abstract

Enriched environment (EE) has an important role in the development and plasticity of the brain. In this study, we investigated the maintenance of early EE exposure-induced changes of spatial sensitivity, and the possible underlying mechanisms of this maintenance. We found that, compared with the age-matched control, the spatial sensitivity of A1 neurons was still enhanced after EE rats had been returned to the normal condition for 2 months. The enhancement was expressed by a sharper frequency tuning curve, smaller spatial receptive field, and a more selective directional curve of the early EE-exposed rats. Simultaneously, we detected significant increases in GABAA receptor α1, β3 subunits; NMDA receptor NR2A, NR2B subunits; AMPA receptor GluR2 subunit protein expression; and in the ratios of GABAAα1/GABAAα3 and NR2A/NR2B. In particular, the expression ratio change of the GABAAα1/GABAAα3 was significant greater than that of NR2A/NR2B in early EE-exposed rats. These observations indicate that the persistent higher expression levels of the GABAergic and glutamatergic receptors expression induced by early EE exposure, especially enhancement of GABAergic inhibition in the auditory cortex, might be responsible for the maintenance of improved effects in auditory spatial sensitivity after the rats had been returned to the normal condition.

Research highlights

► The maintenance of enriched environment-induced changes of auditory cortex was studied in this paper. ► We used electrophysiological and biochemistry methods to investigate the phenomenon and the possible underlying mechanism. The results of both techniques indicated that the EE-induced plasticity could last for at least two months at both cellular and molecular levels. ► The expression alterations of several inhibitory/excitatory receptor subunits in the auditory cortex might be responsible for the enhanced spatial sensitivity maintenance which induced by early EE exposure.

Introduction

Enriched environment (EE) has an important role in the development and plasticity of the brain. The variety of effects on the brain, which have been demonstrated at the cellular, molecular, anatomical, physiological, and behavioral levels, suggest that EE accelerates the development and enhances the structural and functional plasticity of the brain (Berardi et al., 2003, Cai et al., 2009, Del Arco et al., 2007, Diamond, 2001, Diamond et al., 1966, Petrosini et al., 2009, Rampon, Jiang et al., 2000, Rampon, Tang et al., 2000, van Praag et al., 2000).

Several studies of the auditory cortex have concluded that EE might increase response strength and selectivity, but decrease the threshold and latency of auditory responses (Engineer et al., 2004, Percaccio et al., 2007, Percaccio et al., 2005). Sound localization is one of the most important tasks performed by the animal auditory system (Knudsen, 1999, Knudsen et al., 2000, Masterton and Imig, 1984, Parsons et al., 1999, Seidl and Grothe, 2005, Zhou and Sun, 2006). Our previous studies have shown that early postnatal EE enhances the directional sensitivity of neurons in the rat primary auditory cortex, such as a smaller spatial receptive field, sharper frequency tuning curve and directional selective curve. The behavioral experiment also found that the EE might improve the number of correct scores, decreasing the reaction time and azimuth deviation in sound-discrimination tasks. Interestingly, the improvement of behavioral performance lasted for at least 2 months after the animals had been returned to the normal condition (Cai et al., 2009). However, it remains unknown whether and how the enhancement of auditory spatial sensitivity induced by early EE exposure maintained in the primary auditory cortex occurred.

Despite several studies, the mechanisms responsible for enhancement of spatial tuning caused by early EE remain unclear. Several mechanisms, including γ-aminobutyric acid (GABA)-mediated inhibition and N-methyl-d-aspartate (NMDA)-mediated excitation, are crucial for experience-dependent developmental plasticity. Previous studies have shown that early postnatal experience and environment significantly affect NMDA receptor expression in the visual cortex (Chen and Bear, 2007, Philpot et al., 2001, Quinlan, Olstein et al., 1999, Quinlan, Philpot et al., 1999). Previous studies have indicated that mice reared in EE from birth have higher levels of brain-derived neurotrophic factor (BDNF) protein in the visual cortex, which accelerate the development of the inhibitory GABAergic system by influencing receptive field development and synaptic plasticity (Cancedda et al., 2004, Huang et al., 1999, Sale et al., 2004, Sale et al., 2007). Our recent study also found that early, continuous noise rearing induces significant decreases in GAD 65 and GABAA receptor α1 subunit expression and increases GABAA receptor α3 subunit expression (Xu, Yu, Cai, Zhang, & Sun, 2009). These observations suggest that the developmental changes of glutamatergic and GABAergic play important roles in the structural and functional plasticity of the brain.

These findings have led us to hypothesize that the improvement of auditory spatial sensitivity induced by early EE exposure might be maintained in the auditory cortical neurons after the animal has been returned to the normal condition, and go with the developmental changes of both GABA-mediated inhibition and NMDA-mediated excitation. To test this hypothesis, we first measured the spatial sensitivity of the auditory neuron to determine whether there is any similarity to the behavioral task performance. If so, we would then examine the expression of the GABAA receptor (regarded as an important factor in spatial sensitivity) and the NMDA receptor and AMPA receptor subunits. We hope this study will help us understand the molecular basis of the maintenance of functional plasticity in the auditory cortex after EE exposure.

Section snippets

Animals

Sprague–Dawley (SD) rats were used in the present study. The EE rats with their mother were first raised in the enriched condition from postnatal day 7 (P7) to P56, and then moved to the normal reared condition until approximately P115. The control (CON) rats were raised under normal conditions from birth until approximately P115 (Fig. 1). A reverse 12-h light/dark cycle and constant humidity and temperature conditions were maintained for both groups.

EE conditions and normal conditions were the

The enhancement of auditory spatial sensitivity of A1 neurons by early EE exposure lasted for at least 2 months after returning to normal conditions

Observations were based on 153 single neurons from the A1 of the EE rats and 157 single neurons from the age-matched control rats. Most histologically identified sites were located in layers II/III to IV of the primary auditory cortex (A1) (recording depth was among 300–1200 μm from surface). CFs were broadly distributed in each sample, ranging from 1 kHz to 30 kHz and divided into three categories stepped by 1.5 octaves.

Discussion

Results of the present study indicate that the enhancement effects of auditory spatial sensitivity by early EE exposure were maintained in the primary auditory cortex after it returned to the normal condition and that there were marked increases in GABAA receptor α1, β3 subunits, NMDA receptor NR2A, NR2B subunits, and AMPA GluR2 subunit protein expression.

It has been reported that EE has a remarkable influence on the developmental plasticity of the visual system. The most striking effect on

Acknowledgments

This work was supported by the Nature Science Foundation of China (NSFC No. 30970984), Shanghai Rising-Star Program (No. 09QH1400900), and New Century Excellent Talents at the University of State Education Ministry of China (NCET-07-0298). We thank Lu Zhang for his help with the statistical analysis by Matlab software.

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