Introduction Fear memory generalization is regarded as the core characteristic of posttraumatic stress disorder (PTSD) development. However, the mechanism that contributes to the generalization of conditioned fear memory is still unclear. The generalization is generally considered to be a mismatch that occurs during memory consolidation. Methods Foot shocks and tones were given as unconditioned stress and conditioned stress, respectively for fear conditioning training. Immunofluorescence staining, western blotting and qPCR were performed to determine the expression of different genes in amygdala of mice after fear conditioning training. Cycloheximide was used as a protein synthesis inhibitor and 2-methyl-6-phenylethynyl-pyridine was injected for mGluR5 inhibition. Results Fear conditioning using caused incremental generalization, which was clearly observed during training. The density of c-Fos + cells or the synaptic p-NMDAR expression did not differ with stress intensities. Strong-shock fear conditioning could induce significant mGluR5 de novo synthesis in the amygdala, which was not observed in the weak-shock group. Inhibition of mGluR5 impaired fear memory generalization induced by strong-shock fear conditioning, but the generalization level induced by weak-shock training was enhanced. Discussion These results indicated that mGluR5 in the amygdala is critical to the function of inappropriate fear memory generalization and suggested that this may be a potential target for the treatment of PTSD.
Vincristine (VCR) is a commonly used clinical anti-cancer drug, but it can also induce neurotoxicity and cause vincristine-induced neuropathic pain (VINP). The metabotropic glutamate receptor 5 (mGluR5) within spinal dorsal horn neurons regulates the transmission of pain mediated by glutamate. In this study, we investigated for the first time the role of mGluR5 in the transmission of noxious information in VINP. Expression of mGluR5 protein was significantly increased in the spinal cord from days 6 to 14 after VCR injection. Immunofluorescence double staining showed that mGluR5 colocalized with the neuron-specific marker NeuN. The intrathecal administration of MPEP (a specific antagonist of mGluR5) or DHPG (an agonist of mGluR5) influenced the pain threshold and mGluR5 protein expression in VINP mice. The expression of c-Fos protein was also affected by MPEP. Furthermore, simulated blockade of intracellular mGluR5 site by intrathecal injection of small interfering RNA (siRNA) of the excitatory amino acid transporter 3 (EAAT3) reduced mechanical allodynia and thermal hyperalgesia and suppressed the expression of mGluR5 and c-Fos proteins. The results collectively indicate that mGluR5 site in spinal dorsal horn neurons may be involved in the regulation of intracellular nociceptive signal transmission in VINP, and the expression of c-Fos largely depends on the intracellular mGluR5.
Gamma oscillations have been frequently observed in levodopa-induced dyskinesia (LID), manifest as broadband (60-120 Hz) and narrowband (80-110 Hz) gamma activity in cortico-striatal projection. We investigated the electrophysiological mechanisms and correlation of gamma oscillations with dyskinesia severity, while assessing the administration of fenobam, a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, in regulating dyskinesia-associated gamma activity. We conducted simultaneous electrophysiological recordings in Striatum (Str) and primary motor cortex (M1), together with Abnormal Involuntary Movement Scale scoring (AIMs). Phase-amplitude coupling (PAC), power, coherence, and Granger causality analyses were conducted for electrophysiological data. The findings demonstrated increased beta oscillations with directionality from M1 to Str in parkinsonian state. During on-state dyskinesia, elevated broadband gamma activity was modulated by the phase of theta activity in Str, while M1 → Str gamma causality mediated narrowband gamma oscillations in Str. Striatal gamma power (both periodic and aperiodic power), periodic power, peak frequency, and PAC at 80 min (corresponding to the peak dyskinesia) after repeated levodopa injections across recording days (day 30, 33, 36, 39, and 42) increased progressively, correlating with total AIMs. Additionally, a time-dependent parabolic trend of PAC, peak frequency and gamma power was observed after levodopa injection on day 42 from 20 to 120 min, which also correlated with corresponding AIMs. Fenobam effectively alleviates dyskinesia, suppresses enhanced gamma oscillations in the M1-Str directionality, and reduces PAC in Str. The temporal characteristics of gamma oscillations provide parameters for classifying LID severity. Antagonizing striatal mGluR5, a promising therapeutic target for dyskinesia, exerts its effects by modulating gamma activity.
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