Synaptic Plasticity Of Prefrontal Cortex And Learning Memory In NR1 Knockout Mice

Increasing evidences indicate that N-methyl-D-aspartic acid (NMDA) receptors are the molecular switch for synaptic plasticity and learning memory. The NMDA receptors are heteromeric complexes consisting of subunit NR1, various NR2 subunits (A, B, C and D) and NR3 subunits (A and B). As the core subunit of NMDA receptor, NR1 subunits are expressed in various brain regions. The role of NMDA receptors and its subunits in synaptic plasticity and learning and memory has been extensively studied in the hippocampus. Belonging to the forebrain, the prefrontal cortex and hippocampus play important roles in the high cognition function of brain. Previous studies have demonstrated that prefrontal cortex plays important roles in short-term storage of information, behavioral flexibility, attention regulation and decision making. And NMDA receptors play important roles in the prefrontal functions. NR1 subunits, the core subunit of NMDA receptor, are extensively expressed in the prefrontal cortex. However, the role of NR1 subunits in the prefrontal synaptic plasticity and related cognition function is not well characterized.Therefore, we used vitro field potential recording and behavioral techniques to investigate the prefrontal synaptic plasticity, spatial working memory, behavioral flexibility and emotional behaviors of forebrain-specific NR1 knockout mice. The major findings are as follows:1 Investigation of prefrontal synaptic transmission in NR1 knockout mice1.1 The basic synaptic transmissionThis study investigated the prefrontal synaptic plasticity of forebrain-specific NR1 knockout mice by using the vitro field potential recording technique. The results from the input-output and paired pulse depression curves suggest that postsynaptic AMPA receptors and presynaptic functions are normal in the prefrontal cortex of NR1 knockout mice.1.2 Prefrontal synaptic plasticity of NR1 knockout mice Prefrontal long-term potentiation (LTP) induced by high frequency stimulation (two trains of 100 Hz with ls duration and 30 s interval) is abolished in slices of NR1 knockout mice. Prefrontal long-term depression (LTD) induced by low frequency stimulation (1 Hz,900 pulses) and paired-pulse low frequency stimulation (200 ms PPI,900 pairs) are normal in prefrontal slices of NR1 knockout mice. These results indicate that NR1 is critical in the induction of long-term potentiation in prefrontal cortex.2 Behavior and emotion of NR1 knockout miceThe present study investigated the effects of NR1 knockout on behavior and emotion using open field, elevated plus-maze and light-dark transition. NR1 knockout mice showed higher locomotor activity than wildtype littermates in 1 h open field. The results from light-dark transition and elevated plus-maze showed that emotion of NR1 knockout mice was normal.3 Prefrontal cortex related cognitive function of NR1 knockout mice3.1 Spatial working memoryWe used modified water maze and spontaneous alternation Y-maze to study the spatial working memory of NR1 knockout mice. The results show that the NR1 knockout mice have normal spatial working memory, which indicate that NR1 in the forebrain may not influence the spatial working memory.3.2 Behavioral flexibilityBy employing four-arm cross-maze, we investigated the behavioral flexibility of NR1 knockout mice. The results indicate that NR1 knockout in the forebrain may impair the behavioral flexibility in mice. In summary, forebrain NR1 knockout may disrupt prefrontal LTP and behavioral flexibility of mice, suggesting that the abolished synaptic plasticity may underlie the performance deficits in behavioral flexibility. In addition, NR1 knockout mice show higher locomotor activity but normal emotional behavior. Our results maybe helpful to understand cellular and molecular mechanisms of behavioral flexibility.