Study On The Synaptic Plasticity And Related Functions In The Prefrontal Cortex Of NR2A Transgenic Mice

Previous studies have demonstrated that the prefrontal cortex (PFC) plays an important role in working memory, emotion, decision making, attention regulation and behavioral inhibition. And deficits in the PFC might be involved in the pathophysiology of psychiatric and neurological disorders such as schizophrenia, mood disorders, parkinson's disease and attention deficit hyperactivity disorder.N-methyl-D-aspatate receptors (NMDARs) represent a subclass of excitatory glutamate receptors that play a critical role in synaptic transmission, plasticity and neuronal development. The NMD A receptors are heteromeric complexes consisting of subunit (NR1), various NR2 subunits (A-D) and NR3 subunits (A,B). The formation of functional NMDA receptors requires a combination of NR1 subunits and at least one of NR2 subunits, and the type of the NR2 subunit critically determines additional biophysical and pharmacological properties of NMDARs. Like in the hippocampus, NR2A and NR2B subunits are predominantly expressed in the PFC. However, the role of NR2A subunits for the prefrontal cortical plasticity and related function is not well characterized.Administration of noncompetitive NMDA receptor antagonists, such as phencyclidine (PCP) and kitamine, induces a broad range of schizophrenic-like symptomatology and impaired working memory, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. The further study shows that sub-chronic PCP treatment in the developing rat caused an increase in NR1 and NR2A expression. Moreover, mice lacking NR2A subunits exhibited hyperlocomotion in a novel environment, deficits in working memory and impaired LTP. These data suggest that the down-regulation of NR2A subunits may evoke the schizophrenia-like behavior and impaired prefrontal cortex-related functions. It would be interesting to know, whether upregulation of NR2A subunits in the PFC would affect the prefrontal synaptic plasticity and prefrontal cortex-related functions. In the present study, we employed molecular techniques, electrophysiologial recordings and a series of behavioral tasks to investigate this issue. Results:(1) Study on NR2A expression in the prefrontal cortex of NR2A transgenic mice.The data from Real-time PCR, western-blot, immunohistochemistry experiment revealed that the expression of NR2A subunits increased in the prefrontal cortex of the transgenic mice, while no significant alternation was found in the expression of NR1 and NR2B subunits.(2) Study on prefrontal synaptic plasticity in NR2A transgenic mice.1) The basic synaptic transmission. We evaluated the effect of NR2A overexpression on basal synaptic transmission in the prefrontal cortex. No significant differences was measured in the input-output relationship of synapse responses and paired-pulse depression between the two groups, indicating the presynaptic function and postsynaptic AMPA receptors are normal in NR2A transgenic mice.2) Study on synaptic plasticity in the prefrontal cortex of NR2A transgenic mice. Prefrontal long-term potentiation (LTP) induced by high frequency stimulation (HFS) and theta burst stimulation (TBS) were significnat smaller in NR2A transgenic slices than wild-type slices. In addition, long-term depression (LTD) evoked by low frequency stimulation (900 pulses, 1Hz; 900 pulses,3Hz) was also impaired in the transgenic mice, and this impairment was restored by the bath application of NVP-AAM007 (0.4um), a selective antagonist of the NR2A subunit.These data indicate that overexpression of NR2A subunits impairs bidirectional synaptic plasticity of the prefrontal cortex.(3) Study on the schizophrenia-like behavior in NR2A transgenic mice.A series of behavior tasks including open field, prepulse inhibition test, resident-intruder test and nest building test were employed to test whether NR2A transgenic mice exhibit schizophrenia-like behavior. We found that distinct schizophrenia-related symptoms emerged in NR2A transgenic mice, including increased stereotypy time, social withdraw, nest-building deficits. Prepulse inhibition was also impaired in NR2A transgenic mice. The treatment of "atypical" antipsychotic drug clozapine can ameliorate some related abnormal behavior in NR2A transgenic mice. These findings support a model in which increased NR2A subunits expression results in schizophrenia-like behavior.(4) The study on the cognitive function in NR2A transgenic mice.The present study investigates the effects of NR2A subunits overexpression on prefrontal cortex-related cognitive function using novel object recognition test, T maze, water maze, conditioned taste aversion task and fear conditioning test. The working memory deficit in NR2A transgenic mice which was considered to be a core deficit in schizophrenia was observed in T-maze and working memory version of water maze, and the associative memory of NR2A transgenic mice in conditioned taste aversive test and fear conditioning test was also impared. In addition, NR2A transgenic mice exhibited impaired recognition memory and reverse learning in novel object recognition test and water maze reverse learning task. This data indicate that NR2A transgenic mice which show schizophrenia-like behavior also had deficits in the prefrontal cortex-related memory.Conclusion:The overexpression of NR2A subunits impairs the prefrontal long-term synaptic plasticity in NR2A transgenic mice. The hypofunticon of PFC resulted in cognitive deficits and schizophrenia-like behavior in NR2A transgenic mice.