European Journal of Neuroscience最新文献

Ilaria, S, Tamara, D, Antonella, J, Elena, M. Role of mitochondria-endoplasmic reticulum contacts in neurodegenerative, neurodevelopmental and neuropsychiatric conditions. The European Journal of Neuroscience 2024; 60(5): 5040–5068. https://doi.org/10.1111/ejn.16485

The author list is incorrectly reported, the authors' first names have been exchanged with their surnames. It should appear as follows:

Serangeli I, Diamanti T, De Jaco A, Miranda E.

And in the extended version as follows:

Ilaria Serangeli, Tamara Diamanti, Antonella De Jaco, Elena Miranda.

We apologise for this error.

Neurodegenerative diseases are characterized by progressive deterioration of the nervous system. Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are prominently life-threatening examples of neurodegenerative diseases. The complexity of the pathophysiology in neurodegenerative diseases causes difficulties in diagnosing. Although the drugs temporarily help to correct specific symptoms including memory loss and degeneration, a complete treatment has not been found yet. New therapeutic approaches have been developed to understand and treat the underlying pathogenesis of neurodegenerative diseases. With this purpose, clustered-regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) technology has recently suggested a new treatment option. Editing of the genome is carried out by insertion and deletion processes on DNA. Safe delivery of the CRISPR/Cas system to the targeted cells without affecting surrounding cells is frequently investigated. Extracellular vesicles (EVs), that is exosomes, have recently been used in CRISPR/Cas studies. In this review, CRISPR/Cas and EV approaches used for diagnosis and/or treatment in AD, PD, ALS, and HD are reviewed. CRISPR/Cas and EV technologies, which stand out as new therapeutic approaches, may offer a definitive treatment option in neurodegenerative diseases.

The biological clock of the suprachiasmatic nucleus (SCN) orchestrates circadian (approximately daily) rhythms of behaviour and physiology that underpin health. SCN cell-autonomous time-keeping revolves around a transcriptional/translational feedback loop (TTFL) within which PERIOD (PER1,2) and CRYPTOCHROME (CRY1,2) proteins heterodimerise and suppress trans-activation of their encoding genes (Per1,2; Cry1,2). To explore its contribution to SCN time-keeping, we used adeno-associated virus–mediated translational switching to express PER2 (tsPER2) in organotypic SCN slices carrying bioluminescent TTFL circadian reporters. Translational switching requires provision of the non-canonical amino acid, alkyne lysine (AlkK), for protein expression. Correspondingly, AlkK, but not vehicle, induced constitutive expression of tsPER2 in SCN neurons and reversibly and dose-dependently suppressed pPer1-driven transcription in PER-deficient (Per1,2-null) SCN, illustrating the potency of PER2 in negative regulation within the TTFL. Constitutive expression of tsPER2, however, failed to initiate circadian oscillations in arrhythmic PER-deficient SCN. In rhythmic, PER-competent SCN, AlkK dose-dependently reduced the amplitude of PER2-reported oscillations as inhibition by tsPER2 progressively damped the TTFL. tsPER2 also dose-dependently lengthened the period of the SCN TTFL and neuronal calcium rhythms. Following wash-out of AlkK to remove tsPER2, the SCN regained TTFL amplitude and period. Furthermore, SCN retained their pre-washout phase: the removal of tsPER2 did not phase-shift the TTFL. Given that constitutive tsCRY1 can regulate TTFL amplitude and period, but also reset TTFL phase and initiate rhythms in CRY-deficient SCN, these results reveal overlapping and distinct properties of PER2 and CRY1 within the SCN, and emphasise the utility of translational switching to explore the functions of circadian proteins.

Menopause weakens the brain's structural integrity and increases its susceptibility to a range of degenerative and mental illnesses. 17β estradiol (17βE2) exhibits potent neuroprotective properties. Exogenous estrogen supplementation provides neuroprotection, but the findings presented by the Million Women Study (MWS) and the Women's Health Initiative (WHI), as well as the increased risk of endometrial cancer, breast cancer and venous thromboembolism associated with estrogen use, have cast doubt on its clinical use for neurological disorders. Thus, the objective of our review article is to compile all in vitro and in vivo studies conducted till date demonstrating the neuroprotective potential of nonfeminizing estrogens. This objective has been achieved by gathering various research and review manuscripts from different records such as PubMed, Embase, Scopus, Google Scholar, Web of Science and OVID, using different terms like ‘estrogen deficiency, 17β estradiol, non-feminising estrogens, and brain disorder’. However, recent evidence has revealed the contribution of numerous non-estrogen receptor-dependent pathways in neuroprotective effects of estrogen. In conclusion, synthetic nonfeminizing estrogens that have little or no ER binding but are equally powerful (and in some cases more potent) in delivering neuroprotection are emerging as viable and potential alternatives.

The relationship between external feedback and cognitive and neurophysiological performance has been extensively investigated in social neuroscience. However, few studies have considered the role of positive and negative external social feedback on electroencephalographic (EEG) and moderate stress response. Twenty-six healthy adults underwent a moderately stressful job interview consisting of a modified version of the Trier Social Stress Test. After each preparation, feedback was provided by an external committee, ranging from positive to negative with increasing impact on subjects. Stress response was measured by analysing response times (RTs) during the speech phase, while cognitive performance was assessed using a Stroop-like task before and after the test. Results indicate that RTs used to deliver the final speeches with negative feedback were significantly lower compared with those used for the initial speech with positive feedback. Moreover, a generalized improvement in Stroop-like task performance was observed in the post-SST compared with the pre-SST. Consistent with behavioural results, EEG data indicated greater delta, theta, and alpha band responses in right prefrontal and left central areas, and for delta and theta bands, also in parietal areas in response to positive feedback compared with aversive-neutral feedback, highlighting greater cognitive effort required by the former. Conversely, an increase in these bands in right and left temporal and left occipital areas was observed following negative and aversive feedback, indicative of an adaptive response to stress and emotion-regulatory processes. These findings suggest that negative social feedback in moderately stressful and noncritical conditions could contribute to improving individual cognitive performance.

A whole-cell patch-clamp study was carried out to investigate membrane and synaptic properties of cholinergic interneurons in the striatum of aristaless-related homeobox gene (ARX) mutant mice. Brain slices were prepared from mice knocked in two types of ARX, P355L (PL) and 333ins (GCG)7 (GCG). The input resistance of cholinergic interneurons in PL or GCG mice was significantly smaller than that in wild type (WT), whereas resting membrane potential, threshold of action potentials, spontaneous firing rate, sag ratio or afterhyperpolarization of the mutant mice were not significantly different from those of WT mice. In GCG mice, NMDA/AMPA ratio of excitatory postsynaptic currents (EPSCs) evoked in cholinergic interneurons was significantly smaller than that in WT and PL mice, whereas the ratio between PL and WT mice was not significantly different. Although inhibitory effects induced by dopamine D2-like receptor activation on the inhibitory postsynaptic currents (IPSCs) were not significantly different between WT and PL or GCG mice, increase in the paired pulse ratio of IPSCs by dopamine D2-like receptor activation was abolished in PL and GCG mice. The present results have found abnormalities of neuronal activities as well as its modulation in the basal ganglia in ARX mutant mice, clarifying basic mechanisms underlying related disorders.

In this work, we cloned and functionally expressed two novel GABA_A receptor subunits from Procambarus clarkii crayfish. These two new subunits, PcGABA_A-α and PcGABA_A-β2, revealed significant sequence homology with the PcGABA_A-β subunit, previously identified in our laboratory. In addition, PcGABA_A-α subunit also shared a significant degree of identity with the Drosophila melanogaster genes DmGRD (GABA and glycine-like receptor subunits of Drosophila) as well as PcGABA_A-β2 subunit with DmLCCH3 (ligand-gated chloride channel homolog 3). Electrophysiological recordings showed that the expression in HEK cells of the novel subunits, either alone or in combination, failed to form functional homo- or heteromeric receptors. However, the co-expression of PcGABA_A-α with PcGABA_A-β evoked sodium- or chloride-dependent currents that accurately reproduced the time course of the GABA-evoked currents in the X-organ neurons from crayfish, suggesting that these GABA subunits combine to form two types of GABA receptors, one with cationic selectivity filter and the other preferentially permeates anions. On the other hand, PcGABA_A-β2 and PcGABA_A-β co-expression generated a chloride current that does not show desensitization. Muscimol reproduced the time course of GABA-evoked currents in all functional receptors, and picrotoxin blocked these currents; bicuculline did not block any of the recorded currents. Reverse transcription polymerae chain reaction (RT-PCR) amplifications and FISH revealed that PcGABA_A-α and PcGABA_A-β2 are predominantly expressed in the crayfish nervous system. Altogether, these findings provide the first evidence of a neural GABA-gated cationic channel in the crayfish, increasing our understanding of the role of these new GABA_A receptor subunits in native heteromeric receptors.

Phosphoinositides, such as PI(4,5)P₂, are known to function as structural components of membranes, signalling molecules, markers of membrane identity, mediators of protein recruitment and regulators of neurotransmission and synaptic development. Phosphatidylinositol 4-kinases (PI4Ks) synthesize PI4P, which are precursors for PI(4,5)P₂, but may also have independent functions. The roles of PI4Ks in neurotransmission and synaptic development have not been studied in detail. Previous studies on PI4KII and PI4KIIIβ at the Drosophila larval neuromuscular junction have suggested that PI4KII and PI4KIIIβ enzymes may serve redundant roles, where single PI4K mutants yielded mild or no synaptic phenotypes. However, the precise synaptic functions (neurotransmission and synaptic growth) of these PI4Ks have not been thoroughly studied. Here, we used PI4KII and PI4KIIIβ null mutants and presynaptic-specific knockdowns of these PI4Ks to investigate their roles in neurotransmission and synaptic growth. We found that PI4KII and PI4KIIIβ appear to have non-overlapping functions. Specifically, glial PI4KII functions to restrain synaptic growth, whereas presynaptic PI4KIIIβ promotes synaptic growth. Furthermore, loss of PI4KIIIβ or presynaptic PI4KII impairs neurotransmission. The data presented in this study uncover new roles for PI4K enzymes in neurotransmission and synaptic growth.

Monitoring the reality status of conscious experience is essential for a human being to interact successfully with the external world. Despite its importance for everyday functioning, reality monitoring can systematically become erroneous, for example, while dreaming or during hallucinatory experiences. To investigate brain processes associated with reality monitoring occurring online during an experience, i.e., perceptual reality monitoring, we assessed EEG microstates in healthy, young participants. In a within-subjects design, we compared the experience of reality when being confronted with dream-like bizarre elements versus realistic elements in an otherwise highly naturalistic real-world scenario in immersive virtual reality. Dream-like bizarreness induced changes in the subjective experience of reality and bizarreness, and led to an increase in the contribution of a specific microstate labelled C′. Microstate C′ was related to the suspension of disbelief, i.e. the suppression of bizarre mismatches. Together with the functional interpretation of microstate C′ as reported by previous studies, the findings of this study point to the importance of prefrontal meta-conscious control processes in perceptual reality monitoring.