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Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, is considered a potential therapy for treatment-resistant depression. The synaptic mechanism of iTBS has long been known to be an effective method to induce long-term potentiation (LTP)-like plasticity in humans. However, there is limited evidence as to whether the antidepressant effect of iTBS is associated with change in synaptic function in the prefrontal cortex (PFC) in preclinical study. Hence, we applied an antidepressant (i.e., fluoxetine)-resistant depression rat model induced by severe foot-shocks to investigate the antidepressant efficacy of iTBS in the synaptic pathology. The results showed that iTBS treatment improved not only the impaired LTP, but also the aberrant long-term depression in the PFC of antidepressant-resistant depression model rats. Moreover, the mechanism of LTP improvement by iTBS involved downstream molecules of brain-derived neurotrophic factor, while the mechanism of long-term depression improvement by iTBS involved downstream molecules of proBDNF. The aberrant spine morphology was also improved by iTBS treatment. This study demonstrated that the mechanism of the iTBS paradigm is complex and may regulate not only excitatory but also inhibitory synaptic effects in the PFC.

Treatment-resistant depression (TRD) is a major public health issue, as it is common for patients with depression to fail to respond to adequate trials of antidepressants. However, a well-established animal model of TRD is still warranted. The present study focused on selective serotonin reuptake inhibitor (SSRI) resistance, and aimed to investigate whether higher levels of traumatic stress caused by greater numbers of foot-shocks may lead to severe depression and to examine the feasibility of this as an animal model of SSRI-resistant depression. To reveal the correlation between traumatic stress and severe depression, rats received 3, 6 and 10 tone (conditioned stimulus, CS)–shock (unconditioned stimulus, US) pairings to mimic mild, moderate, and severe traumatic events, and subsequent depressive-like behaviors and protein immunocontents were analyzed. The antidepressant efficacy was assessed for ketamine and SSRI (i.e., fluoxetine) treatment. We found that only the severe stress group presented depressive-like behaviors. Phosphorylation of extracellular signal-regulated kinases (ERKs) was decreased in the amygdala and prefrontal cortex (PFC). The immunocontents of GluA1 and PSD 95 were increased in the amygdala and decreased in the PFC. Moreover, the glutamate-related abnormalities in the amygdala and PFC were normalized by single-dose (10 mg/kg, i.p.) ketamine treatment. In contrast, the depressive-like behaviors were not reversed by 28 days of fluoxetine treatment (10 mg/kg, i.p.) in the severe stress group. Our data demonstrated that high levels of traumatic stress could lead to SSRI-resistant depressive symptoms through impacts on the glutamatergic system, and that this rat model has the potential to be a feasible animal model of SSRI-resistant depression.

Valproic acid (VPA)-exposed rat offspring have demonstrated autism spectrum disorder (ASD) phenotypes and impaired N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) in the lateral nucleus of the amygdala. NMDAR partial agonist D-cycloserine (DCS) has been reported to act as a cognitive enhancer by increasing the NMDAR response to improve autistic-like phenotypes in animals. However, the mechanism of DCS in alleviating the ASD is still unknown. Using combined behavioral, electrophysiological, and molecular approaches, we found that DCS administration rescued social interaction deficits and anxiety/repetitive-like behaviors observed in VPA-exposed offspring. In the amygdala synapses, DCS treatment reversed the decreased paired pulse ratio (PPR) and the impaired NMDAR-dependent LTD, increased the frequency and amplitude of miniature excitatory post-synaptic currents (mEPSCs), and resulted in a higher dendritic spine density at the amygdala synapses in the VPA-exposed offspring. Moreover, we found that DCS facilitated the removal of GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (GluA2/AMPARs) by inducing NMDAR-dependent LTD in the VPA-exposed offspring. We further established that the effects of DCS treatment, including increased GluA2/AMPAR removal and rescues of impaired social behavior, were blocked by Tat-GluA23Y, a GluA2-derived peptide that disrupted regulation of AMPAR endocytosis. These results provided the first evidence that rescue of the ASD-like phenotype by DCS is mediated by the mechanism of GluA2/AMPAR removal in VPA-exposed rat offspring.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social interaction impairment, stereotypical/repetitive behaviors and emotional deregulation. The endocannabinoid (eCB) system plays a crucial role in modulating the behavioral traits that are typically core symptoms of ASD. The major molecular mechanisms underlying eCB-dependent long-term depression (eCB-LTD) are mediated by group 1 metabotropic glutamate receptor (mGluR)-induced removal of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Recently, modulation of anandamide (AEA), one of the main endocannabinoids in the brain, has been reported to alter social behaviors in genetic models of ASD. On this basis, we investigated the effects of treatment and the synaptic mechanism underlying AEA-mediated signaling in prenatal exposure to valproic acid (VPA) in rats. We found that the social deficits, repetitive behaviors and abnormal emotion-related behaviors in VPA-exposed offspring were improved after treatment with an inhibitor of AEA degrading enzyme, URB597. Using an integrative approach combing electrophysiological and cellular mechanisms, the results showed that the impaired eCB-LTD, abnormal mGluR-mediated LTD (mGluR-LTD) and decreased removal of AMPAR subunits GluA1 and GluA2 were reversed by URB597 in the prefrontal cortex (PFC) of VPA-exposed offspring. Taken together, these results provide the first evidence that rescue of the ASD-like phenotype by URB597 is mediated by enhancing the mechanism of removal of AMPAR subunits GluA1/2 underlying AEA signaling in the PFC in a VPA-induced model of ASD.

Background Social deficit is a core symptom in autism spectrum disorder (ASD). Although deep brain stimulation (DBS) has been proposed as a potential treatment for ASD, an ideal target nucleus is yet to be identified. DBS at the central thalamic nucleus (CTN) is known to alter corticostriatal and limbic circuits, and subsequently increase the exploratory motor behaviors, cognitive performance, and skill learning in neuropsychiatric and neurodegenerative disorders. Objective We first investigated the ability of CTN-DBS to selectively engage distinct brain circuits and compared the spatial distribution of evoked network activity and modulation. Second, we investigated whether CTN-DBS intervention improves social interaction in a valproic acid–exposed ASD rat offspring model. Methods Brain regions activated through CTN-DBS by using a magnetic resonance (MR)-compatible neural probe, which is capable of inducing site-selective microstimulations during functional MRI (fMRI), were investigated. We then performed functional connectivity MRI, the three-chamber social interaction test, and Western blotting analyses to evaluate the therapeutic efficacy of CTN-DBS in an ASD rat offspring model. Results The DBS-evoked fMRI results indicated that the activated brain regions were mainly located in cortical areas, limbic-related areas, and the dorsal striatum. We observed restoration of brain functional connectivity (FC) in corticostriatal and corticolimbic circuits after CTN-DBS, accompanied with increased social interaction and decreased social avoidance in the three-chamber social interaction test. The dopamine D2 receptor decreased significantly after CTN-DBS treatment, suggesting changes in synaptic plasticity and alterations in the brain circuits. Conclusions Applying CTN-DBS to ASD rat offspring increased FC and altered the synaptic plasticity in the corticolimbic and the corticostriatal circuits. This suggests that CTN-DBS could be an effective treatment for improving the social behaviors of individuals with ASD.

Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid and metabolized by soluble epoxide hydrolase (sEH). The role of EETs in synaptic function in the central nervous system is still largely unknown. We found that pharmacological inhibition of sEH to stabilize endogenous EETs and exogenous 14,15-EET significantly increased the field excitatory postsynaptic potential (fEPSP) response in the CA1 area of the hippocampus, while additionally enhancing high-frequency stimulation- (HFS-) induced long-term potentiation (LTP) and forskolin- (FSK-) induced LTP. sEH inhibitor (sEHI) N-[1-(oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy) phenyl)-urea (TPPU) and exogenous 14,15-EET increased HFS-LTP, which could be blocked by an N-methyl-D-aspartate (NMDA) receptor subunit NR2B antagonist. TPPU- or 14,15-EET-facilitated FSK-mediated LTP can be potentiated by an A1 adenosine receptor antagonist and a phosphodiesterase inhibitor, but is prevented by a cAMP-dependent protein kinase (PKA) inhibitor. sEHI and 14,15-EET upregulated the activation of extracellular signal-regulated kinases (ERKs) and Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII). Phosphorylation of synaptic receptors NR2B andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 was increased by TPPU and 14,15-EET administration. These results indicated that EETs increased NMDAR- and FSK-mediated synaptic potentiation via the AC-cAMP-PKA signaling cascade and upregulated the ERKs and CaMKII, resulting in increased phosphorylation of NR2B and GluR1 in the hippocampus.

The amygdala plays crucial roles in socio-emotional behavior and cognition, both of which are abnormal in autism spectrum disorder (ASD). Valproic acid (VPA)-exposed rat offspring have demonstrated ASD phenotypes and amygdala excitatory/inhibitory imbalance. However, the role of glutamatergic synapses in this imbalance remains unclear. In this study, we used a VPA-induced ASD-like model to assess glutamatergic synapse-dependent long-term depression (LTD) and depotentiation (DPT) in the amygdala. We first confirmed that the VPA-exposed offspring exhibited sociability deficits, anxiety, depression-like behavior, and abnormal nociception thresholds. Then, electrophysiological examination showed a significantly decreased paired-pulse ratio in the amygdala. In addition, both NMDA-dependent LTD and DPT were absent from the amygdala. Furthermore, we found that the levels of glycogen synthase kinase3β (GSK-3β) phosphorylation and β-catenin were significantly higher in the amygdala of the experimental animals than in the controls. Local infusion of phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin into the amygdala reversed the increased phosphorylation level and impaired social behavior. Taken together, the results suggested that NMDA receptor-related synaptic plasticity is dysfunctional in VPA-exposed offspring. In addition, GSK-3β in the amygdala is critical for synaptic plasticity at the glutamatergic synapses and is related to social behavior. Its role in the underlying mechanism of ASD merits further investigation.

Deep brain stimulation (DBS) is known to be a promising treatment for resistant depression, which acts via the serotonin (5-hydroxytryptamine, 5-HT) system in the infralimbic prefrontal cortex (ILPFC). Previous study revealed that dysfunction of brain 5-HT homeostasis is related to a valproate (VPA)-induced rat autism spectrum disorder (ASD) model. Whether ILPFC DBS rescues deficits in VPA-induced offspring through the 5-HT system is not known. Using VPA-induced offspring, we therefore explored the effect of DBS in autistic phenotypes and further investigated the underlying mechanism. Using combined behavioral and molecular approaches, we observed that applying DBS and 5-HT1A receptor agonist treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reversed sociability deficits, anxiety and hyperactivity in the VPA-exposed offspring. We then administered the selective 5-HT1A receptor antagonist N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY 100635), following which the effect of DBS in terms of improving autistic behaviors was blocked in the VPA-exposed offspring. Furthermore, we found that both 8-OH-DPAT and DBS treatment rescued autistic behaviors by decreasing the expressions of NR2B subunit of N-methyl-D-aspartate receptors (NMDARs) and the &beta, 3 subunit of &gamma, aminobutyric acid type A receptors (GABAAR) in the PFC region. These results provided the first evidence of characteristic behavioral changes in VPA-induced offspring caused by DBS via the 5-HT system in the ILPFC.