| Summary: | 碩士 === 國立成功大學 === 藥理學研究所 === 101 === Background: Autism-like phenotypes in the male VPA-exposed offspring has been linked to high glutamatergic neurotransmission in the thalamic-amygdala pathway. Glial cystine/glutamate exchange (system Xc-), which exchanges extracellular cystine for intracellular glutamate, plays a significant role in the maintenance of extracellular glutamate. N-acetylcysteine (NAC) is a cystine prodrug that restores extracellular glutamate by stimulating cysteine system Xc-. Here, we examine the effects of systemic NAC on autism-like phenotypes and neurotransmission in thalamic–amygdala synapses, as well as the involvement of the metabotropic glutamate receptors 2/3 (mGluR2/3).
Methods: In valproate-induced model of autism, the valproate-treated rats received a single intraperitonal injection of 500 mg/kg NaVPA on E12.5. On postnatal day 21, male offspring were tested using serial behavioral tasks, including the social interaction (SI), open field (OF) and elevated plus maze (EPM) tasks. After behavioral tasks, NAC (150 mg/kg, i.p.) or saline was administered once per day for 7 days. After the 7 days injection, the rats were given the same behavioral tests. Twenty-four hours later, the rats were sacrificed for electrophysiological recordings. Intra-amygdala infusion of mGluR2/3 antagonist LY341495 (2ug/0.5ul per side) once per day for 4 days 30min before NAC. One hour after LY341495 injection, the rats were given the same behavioral tests.
Results: Chronic administration of NAC restored the duration and times of social interaction and ameliorated anxiety-like behaviors in VPA-exposed offspring. In amygdala slices, NAC treatment normalized increased frequency of mEPSCs and decreased PPF induced by VPA exposure. The effects of NAC on social interaction and anxiety in VPA-exposed offspring were blocked after intra-amygdala infusion of mGluR2/3 antagonist. Finally, protein levels from rats tissue obtained from VPA-exposured offspring revealed significant changes in the level of mGluR2/3, the active subunit for suppressing glutamatergic neurotransmission, in the amygdala.
Conclusions: The disruption of social interaction, increased anxiety and enhanced presynaptic excitatory transmission in VPA-exposed offspring could be rescued by NAC which depends on the activation of mGluR2/3. These data advance mGluR2/3 receptors as novel targets capable of reversing the autism-like phenotypes in the male VPA-exposed offspring.
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