Synapse最新文献

Aim/hypothesis: Diabetes mellitus has been reported to be a risk factor for cognitive dysfunction, depression, stroke, and seizures. Diabetic pathology is believed to interfere with synaptic plasticity. Synaptic vesicle glycoprotein 2A (SV2A) is a presynaptic vesicular protein and a popular synaptic density imaging marker. We investigated the effect of chronic hyperglycemia on the expression of SV2A in the cerebral cortex and hippocampus of rats and compared it to other presynaptic markers, such as GAP43, Synaptotagmin-1, and SNAP25.

Methods: A single dose of streptozotocin (STZ, 45 mg/kg, i.p.) was administered to adult male rats, resulting in sustained hyperglycemia and reduced plasma insulin levels. Controls were injected with saline, and another STZ group was treated with insulin. Fasting blood glucose (FBG) and fasting plasma insulin (FPI) levels were monitored throughout the observation period, and the level of SV2A was determined by radioligand, [³H]UCB-J, binding capacity using in-vitro autoradiography and by ELISA. Similarly, the tissue concentration of other synaptic proteins GAP43, SNAP25, and SYN1 was measured using ELISA. Quantitative RT-qPCR was performed to measure Sv2a, Sv2b, and Sv2c transcripts. Finally, hippocampal and cortical glutamate levels were measured in all tissues.

Results: [³H]UCB-J binding, SV2A (pg/mg protein) and Sv2a mRNA levels were significantly higher in hyperglycemic rats. The SV2A concentration detected by ELISA and [³H]UCB-J binding showed, as expected, a positive correlation with each other. The same positive and significant correlation was seen between SV2A, FBG, and glutamate l levels across animals (p ≤ 0.001). Notably, there was no difference and no linearity between FBG and other presynaptic markers such as GAP43, Synaptotagmin-1, and SNAP25.

Conclusions: Unlike other synaptic markers (e.g., SNAP25, SYN-1), SV2A levels rise independently of synaptic density, correlating with elevated glutamate and metabolic activity. These findings raise doubt about SV2A's role as a pure synaptic density marker.

Navigation incorporates a continuum of strategies, where the allocentric strategy relies on relationships between environmental landmarks resulting in a cognitive map, and the egocentric strategy revolves around the body position and stimulus response chains with the body as a reference. Although multiple brain regions contribute to navigation, the hippocampus dominates allocentric navigation, whereas the striatum is key for egocentric navigation. Neuromodulators, such as dopamine and acetylcholine, regulate both the hippocampus and striatum to influence behavior, yet their influence on navigational strategy has not been determined. Interindividual differences in strategy preference are known to exist. Building on these pre-existing interindividual differences, this study explored the neuroanatomical underpinnings on navigational strategy variations in rats through a dual-solution T-maze and immunocytochemistry. Surprisingly, interindividual variations eluded explanation through the density of cholinergic neurons supplying acetylcholine to the hippocampus and striatum. Similarly, the soma morphologies of these neurons exhibited no discernible differences. Dopaminergic cell densities in the ventral tegmental area (VTA), projecting to the hippocampus, and substantia nigra pars compacta (SNpc), projecting to the striatum, failed to account for individual variations as well. Nevertheless, allocentric rats displayed higher VTA/SNpc dopamine neuron fusiformity indexes, potentially contributing to computational distinctions underlying interindividual variations in navigation strategies. This study delves into potential explanations and charts promising avenues for future research. A graphical abstract summarizing the main findings of this study is provided.

Psychedelic compounds have gained renewed interest due to their rapid and long-lasting therapeutic effects on stress-related disorders. While the underlying mechanisms of therapeutic actions of psychedelic compounds are still unclear, these drugs are thought to modulate the activity of the serotonergic system, primarily through activating serotonin type 2A receptor (5-HT_2AR) and studies have focused on these actions in the medial prefrontal cortex (mPFC). 25CN-NBOH, a synthetic psychedelic compound with a high binding affinity for 5-HT_2ARs and anti-anxiety actions, has emerged as a valuable tool for investigating the physiological functions mediated by this receptor. This study aimed to investigate the electrophysiological effects of 25CN-NBOH on pyramidal mPFC neurons using whole-cell patch clamp recordings in mouse brain slices. We recorded synaptic events and action potential rates during acute and long-term exposure to two concentrations of 25CN-NBOH. Acute application of 10 µM 25CN-NBOH increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) that was reliant on activation of 5-HT_2AR, and which was not seen upon chronic exposure. A similar effect of 200 nM 25CN-NBOH was not noted. Surprisingly, both 10 µM and 200 nM 25CN-NBOH significantly suppressed the firing rate following acute as well as a longer-term exposure of 1 h. This suppression was independent of 5-HT_2AR activation but was mediated by M-current channels, as evidenced by the reversal of suppression with the M-current blocker XE-991. Our data suggest a complicated dual action of 25CN-NBOH in enhancing excitatory transmission while also reducing excitability. Our data contribute to knowledge regarding the cellular consequence of 5-HT_2AR agonism and contribute to widening our understanding of the potential mechanisms underlying the therapeutic actions of serotonergic psychedelics.

Synaptic degeneration has been linked to cognitive decline. The presynaptic protein, synaptosomal-associated protein 25 kDA (SNAP-25), is crucial for synaptic transmission and has been suggested as a biomarker in Alzheimer's disease (AD). In the current study, we investigated the ability of SNAP-25 to differentiate between heterogenous dementia etiologies and whether SNAP-25 could be a staging marker in AD. SNAP-25 in the cerebrospinal fluid (CSF) from a retrospective (n = 187) and a prospective (n = 134) cohort was investigated with immunoprecipitation mass spectrometry (IP-MS) and single-molecule array (Simoa), respectively. Both cohorts consisted of healthy controls (HC) and patients with cognitive decline of different etiologies. CSF SNAP-25 concentration was higher in AD and non-neurodegenerative diseases (i.e., vascular dementia) compared with controls but did not differ between AD and non-AD neurodegenerative diseases. We found a trend toward an association between SNAP-25 and disease burden when comparing HC, mild cognitive impairment due to AD, and AD. CSF SNAP-25 concentrations were strongly associated with CSF phosphorylated tau (p-tau) concentrations, thus strengthening the link between synaptic dysfunction and tau pathophysiology in AD. Our initial findings suggest that SNAP-25 may be a potential biomarker for differentiating AD from dementia due to other etiologies. However, due to the significant association between SNAP-25 and p-tau proteins, the clinical utility of SNAP-25 as a diagnostic biomarker for AD may be limited, while SNAP-25 may be useful for monitoring disease progression or treatment response.

Hippocampal granule cells express GABAergic and glutamatergic phenotype markers during development; hence, they corelease GABA and glutamate. In the adult, the GABAergic phenotype is switched off; however, increased excitability upregulates the GABAergic phenotype and thus, granule cells corelease glutamate and GABA. Previous work shows that short-term cultures (24 h) of dissociated granule cells prepared from adult rats, which do not express GAD or VGAT, can express these markers when exposed to kainic acid and BDNF. We here test whether the same manipulation enables granule cells to corelease glutamate and GABA in long-term cultures where cells are connected. Interestingly, we find that long-term cultured cells are not able to express the GABAergic phenotype despite presenting it during their development, and with paired recordings, we confirm that granule cells only release glutamate. The development of granule cells in long-term isolation likely deprives them of essential signaling that a normal cellular milieu provides to enable phenotypic change. The molecular mechanisms that could underlie this should be further explored by comparing their development in situ and in cultured conditions.

Genetically encoded fluorescent sensors of neural activity have become a mainstay of basic neuroscience. However, preclinical drug development has been slower to adopt these tools. Recently, we used miniature microscopes to record Ca²⁺ activity in D1 and D2 dopamine receptor-expressing spiny projection neurons (SPNs) in response to antipsychotic drugs or candidates. Despite the fact that most antipsychotics block D2 receptors, clinical efficacy was associated with the normalization of D1-SPN activity under hyperdopaminergic conditions. In this study, we re-processed these data to approximate a fiber photometry signal and asked whether the conclusions were the same. This re-evaluation is important because fiber photometry has several advantages over cellular-resolution imaging. Consistent with our previous finding that bulk and cellular-resolution imaging report distinct SPN Ca²⁺ dynamics, here the two data types suggested reciprocal effects of drug treatment on D1-SPN and D2-SPN Ca²⁺ activity. While amphetamine treatment increased D1-SPN and decreased D2-SPN Ca²⁺ event rates in cellular-resolution data, it increased the fluorescence of individual neurons but decreased their bulk fluorescence in both cell types. Analyzing detected bulk-fluorescence "events" yielded a closer correlation between the bulk and somatic Ca²⁺ fluorescence. However, it did not fully replicate the results of our previous cellular-resolution recordings following amphetamine or antipsychotic drug treatment. Our results highlight important distinctions between cellular-resolution and bulk measurements of in vivo Ca²⁺ activity. While experimenters using in vivo imaging to understand drug effects on neural activity should heed these distinctions, they should also utilize them to gain a more holistic view of drug action.

Parkinson's disease (PD) is a common neurodegenerative disease, and, currently, there is no cure for patients with PD. Studies have shown that Ginkgo biloba extract (EGb) has good neuroprotective effects against PD. The cerebellum is widely involved in cognitive function and may be related to the regulation of static tremors in PD. However, research on the corresponding microstructures is limited. Purkinje cells (PCs) are the only efferent neurons present in the cerebellum, and dendritic spines in PCs are considered the key structures for transmitting neuronal excitatory signals. When neurons are activated, polo-like kinase 2 (PLK2) is expressed, leading to the degradation of spine-associated Rap guanosine triphosphatase activating protein (SPAR) and, ultimately, the loss of postsynaptic density protein 95 (PSD-95), causing changes in the morphology or quantity of dendritic spines. This raises the question of whether the neuroprotective effect of EGb involves the PLK2-SPAR pathway. In this study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish a mouse model of dopamine neuronal injury. Golgi staining was performed to observe the dendritic spine changes. Immunohistochemistry was used to detect the expression of PLK2, SPAR, and PSD-95. The results showed that EGb improves MPTP-induced behavioral changes, dopamine neuronal injury, and dendritic spine damage in mice. In addition, EGb reversed the changes in PLK2, SPAR, and PSD-95 expressions caused by MPTP, revealing the potential mechanism by which EGb improves the condition of patients with PD.

Objective: Anorexia nervosa (AN) is an eating disorder with the second highest mortality of all mental illnesses and high relapse rate, especially among adult females, yet with no accepted pharmacotherapy. A small number of studies have reported that adult females who struggled with severe and relapsing AN experienced sustained remission of the illness following ketamine infusions. Two other reports showed that 30 mg/kg IP ketamine can reduce vulnerability of adolescent mice to activity-based anorexia (ABA), an animal model of AN. However, no study has tested the efficacy of ketamine on adult ABA mice. This study aimed to fill this gap in knowledge.

Methods: Forty-one female mice underwent three cycles of ABA (ABA1, ABA2, and ABA3) to assess relapse vulnerability in adulthood. Of them, 13 received ketamine injections (30 mg/kg, 3 doses) during ABA2 (KET) in adulthood to assess ketamine's acute effects during ABA2 and ketamine's potential for sustained efficacy during ABA3, 10-13 days later. The remaining 28 received vehicle or no injections during ABA2 (CON).

Results: Severe weight loss (>20% of baseline) during ABA3 was observed for 89% of CON but only 69% of KET. Overall wheel running per day was significantly less for KET than CON (p < 0.01) throughout ABA2, including hours of food availability, and these reductions were sustained through ABA3. Food consumption was not altered significantly by ketamine.

Discussion: These findings suggest that ketamine may reduce adult females' vulnerability to ABA and may protect women from AN relapse by reducing hyperactivity.

Brain aging is a multifactorial process that includes a reduction in the biological and metabolic activity of individuals. Oxidative stress and inflammatory processes are characteristic of brain aging. Given the current problems, the need arises to implement new therapeutic approaches. Polyoxidovanadates (POV), as well as curcumin, have stood out for their participation in a variety of biological activities. This work aimed to evaluate the coupling of metavanadate and curcumin (Cuma-MV) on learning, memory, redox balance, neuroinflammation, and cell death in the hippocampal region (CA1 and CA3) and dentate gyrus (DG) of aged rats. Rats 18 months old were administered a daily dose of curcumin (Cuma), sodium metavanadate (MV), or Cuma-MV for two months. The results demonstrated that administration of Cuma-MV for 60 days in aged rats improved short- and long-term recognition memory, decreased reactive oxygen species, and substantially improved lipoperoxidation in the hippocampus. Furthermore, the activity of superoxide dismutase and catalase increased in animals treated with Cuma-MV. It is important to highlight that the treatment with Cuma-MV exhibited a significantly greater effect than the treatments with MV or Cuma in all the parameters evaluated. Finally, we conclude that Cuma-MV represents a potential therapeutic option in the prevention and treatment of cognitive decline associated with aging.

Alcohol consumption is known to affect dopamine (DA) release in the brain, with significant implications for understanding addiction and its neurobiological underpinnings. This meta-analysis examined the effects of acute alcohol administration on striatal DA release in healthy humans as measured with [¹¹C]-raclopride positron emission tomography (PET). Oral alcohol administration was associated with a significant reduction in [¹¹C]-raclopride binding potential (BP_ND) in the ventral striatum (Cohen's d = -0.76), indicative of increased DA release, particularly at lower blood alcohol concentration (BAC) levels (0.08 gm%; Z = 2.34, p = 0.02). That oral alcohol may increase DA release in the ventral striatum at lower doses, and decrease DA release at higher doses, warrants further investigation but appears consistent with other known biphasic, hermetic dose-response effects of alcohol. Additionally, larger effect-sizes in the ventral striatum were observed among those studies which sampled more males than females (Z = -2.08, p = 0.04). While oral alcohol administration was associated with reduced [¹¹C]-raclopride BP_ND in the caudate (Cohen's d = -0.39) and putamen (Cohen's d = -0.37), these findings in the dorsal striatum were more variable and less robust. Our analyses suggests that study design (i.e., counterbalanced versus fixed order) may moderate effect sizes observed in the putamen across studies (Z = -2.27, p = 0.02). By identifying gaps in the current literature and proposing directions for future research, this study hopes to inform the design of future PET studies aimed at quantifying alcohol-induced dopamine release in the striatum of humans.