Timing to be precise? An overview of spike timing-dependent plasticity, brain rhythmicity, and glial cells interplay within neuronal circuits.

In the mammalian brain information processing and storage rely on the complex coding and decoding events performed by neuronal networks. These actions are based on the computational ability of neurons and their functional engagement in neuronal assemblies where precise timing of action potential firing is crucial. Neuronal circuits manage a myriad of spatially and temporally overlapping inputs to compute specific outputs that are proposed to underly memory traces formation, sensory perception, and cognitive behaviors. Spike-timing-dependent plasticity (STDP) and electrical brain rhythms are suggested to underlie such functions while the physiological evidence of assembly structures and mechanisms driving both processes continues to be scarce. Here, we review foundational and current evidence on timing precision and cooperative neuronal electrical activity driving STDP and brain rhythms, their interactions, and the emerging role of glial cells in such processes. We also provide an overview of their cognitive correlates and discuss current limitations and controversies, future perspectives on experimental approaches, and their application in humans.

Impaired spike-gamma coupling of area CA3 fast-spiking interneurons as the earliest functional impairment in the AppNL-G-F mouse model of Alzheimer's disease.

In Alzheimer's disease (AD) the accumulation of amyloid-ß (Aß) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in AppNL-G-F knock-in mice (AppNL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel AppNL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the AppNL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aß plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aß1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aß plaque pathology and cognitive impairment in the AppNL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aß.

Role of Group I Metabotropic Glutamate Receptors in Spike Timing-Dependent Plasticity.

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that exhibit enormous diversity in their expression patterns, sequence homology, pharmacology, biophysical properties and signaling pathways in the brain. In general, mGluRs modulate different traits of neuronal physiology, including excitability and plasticity processes. Particularly, group I mGluRs located at the pre- or postsynaptic compartments are involved in spike timing-dependent plasticity (STDP) at hippocampal and neocortical synapses. Their roles of participating in the underlying mechanisms for detection of activity coincidence in STDP induction are debated, and diverse findings support models involving mGluRs in STDP forms in which NMDARs do not operate as classical postsynaptic coincidence detectors. Here, we briefly review the involvement of group I mGluRs in STDP and their possible role as coincidence detectors.

Bri2 BRICHOS chaperone rescues impaired fast-spiking interneuron behavior and neuronal network dynamics in an AD mouse model in vitro.

Synchronized and properly balanced electrical activity of neurons is the basis for the brain's ability to process information, to learn, and to remember. In Alzheimer's disease (AD), which causes cognitive decline in patients, this synchronization and balance is disturbed by the accumulation of neuropathological biomarkers such as amyloid-beta peptide (Aß42). Failure of Aß42 clearance mechanisms as well as desynchronization of crucial neuronal classes such as fast-spiking interneurons (FSN) are root causes for the disruption of the cognition-relevant gamma brain rhythm (30-80 Hz) and consequent cognitive impairment observed in AD. Here we show that recombinant BRICHOS molecular chaperone domains from ProSP-C or Bri2, which interfere with Aß42 aggregation, can rescue the gamma rhythm. We demonstrate that Aß42 progressively decreases gamma oscillation power and rhythmicity, disrupts the inhibition/excitation balance in pyramidal cells, and desynchronizes FSN firing during gamma oscillations in the hippocampal CA3 network of mice. Application of the more efficacious Bri2 BRICHOS chaperone rescued the cellular and neuronal network performance from all ongoing Aß42-induced functional impairments. Collectively, our findings offer critical missing data to explain the importance of FSN for normal network function and underscore the therapeutic potential of Bri2 BRICHOS to rescue the disruption of cognition-relevant brain rhythms in AD.

Modulation of Kv3.1/Kv3.2 promotes gamma oscillations by rescuing Aß-induced desynchronization of fast-spiking interneuron firing in an AD mouse model in vitro.

KEY POINTS: Gamma oscillations (30-80 Hz) are important for cognitive functions and depend on the synchronized activity of fast-spiking interneurons (FSN), which is crucial for network stability. Gamma oscillations are degraded in Alzheimer's disease (AD) patients exhibiting cognitive impairment, with the degree of cognitive decline correlating with the severity of gamma disruption in response to neurotoxic amyloid-beta peptide (Aß). Small molecule compounds EX15 and RE01 modulate Kv3.1/Kv3.2 potassium channels on FSN, resulting in faster activation kinetics and increased firing frequency, suggesting direct consequences for cognition-relevant gamma oscillations, particularly in a situation where network activity is pathologically compromised in the presence of neurotoxic Aß. Using electrophysiological techniques in an in vitro AD model, we found a significant effect of EX15 and RE01 with respect to counteracting toxic Aß effects on neuronal dynamics, advocating for targeting FSN activity to rescue cognitive performance from impairment caused by neurodegenerative triggers. ABSTRACT: Rhythmic electrical activity in neuronal networks such as gamma oscillations (30-80 Hz) underlies cognitive functions such as sensory perception, attention and memory. Gamma oscillations are disrupted in Alzheimer's disease (AD) patients and animal AD models, with the severity of cognitive decline correlating with the degree of rhythm disruption. Misfolded amyloid-ß peptide (Aß) is assumed to be a key trigger of AD pathology and has been show to de-synchronize action potential firing in fast-spiking interneurons (FSN), which is crucial for entraining neuronal network activity into the gamma rhythm. The synchronizing activity of FSN therefore has become one of the most suitable targets to counteract disease-driven degradation of gamma oscillations and consequent cognitive decline. EX15 and RE01 are small-molecule compounds that modulate Kv3.1/Kv3.2 potassium channels, resulting in faster activation kinetics and increased FSN firing frequency. In the present study, we investigated the potential pro-cognitive effects of EX15 and RE01 by testing their ability to modulate FSN activity during ongoing gamma oscillations in normal and Aß-disrupted network states in mouse hippocampus in vitro. In the compromised, but not the uncompromised, network state with gamma oscillations partially disrupted by Aß, both compounds improve gamma oscillation regularity by promoting re-synchronization of FSN action potential firing. Our data suggest a therapeutic potential for compounds such as EX15 and RE01, which can rescue normal action potential firing parameters in FSN, in the search for disease-modifying drug candidates counteracting the progressive dysfunction of neuronal network dynamics that underlies the cognitive impairment typical of AD and other cognitive brain disorders.

Adenosine Receptor-Mediated Developmental Loss of Spike Timing-Dependent Depression in the Hippocampus.

Critical periods of synaptic plasticity facilitate the reordering and refining of neural connections during development, allowing the definitive synaptic circuits responsible for correct adult physiology to be established. Presynaptic spike timing-dependent long-term depression (t-LTD) exists in the hippocampus, which depends on the activation of NMDARs and that probably fulfills a role in synaptic refinement. This t-LTD is present until the third postnatal week in mice, disappearing in the fourth week of postnatal development. We were interested in the mechanisms underlying this maturation related loss of t-LTD and we found that at CA3-CA1 synapses, presynaptic NMDA receptors (pre-NMDARs) are tonically active between P13 and P21, mediating an increase in glutamate release during this critical period of plasticity. Conversely, at the end of this critical period (P22-P30) and coinciding with the loss of t-LTD, these pre-NMDARs are no longer tonically active. Using immunogold electron microscopy, we demonstrated the existence of pre-NMDARs at Schaffer collateral synaptic boutons, where a decrease in the number of pre-NMDARs during development coincides with the loss of both tonic pre-NMDAR activation and t-LTD. Interestingly, this t-LTD can be completely recovered by antagonizing adenosine type 1 receptors (A1R), which also recovers the tonic activation of pre-NMDARs at P22-P30. By contrast, the induction of t-LTD was prevented at P13-P21 by an agonist of A1R, as was tonic pre-NMDAR activation. Furthermore, we found that the adenosine that mediated the loss of t-LTD during the fourth week of development is supplied by astrocytes. These results provide direct evidence for the mechanism that closes the window of plasticity associated with t-LTD, revealing novel events probably involved in synaptic remodeling during development.

Receptor⁻Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment.

Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term "heteroreceptor complexes" was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A⁻FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A⁻FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A⁻5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1⁻15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1⁻GalR2⁻5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

Presynaptic Spike Timing-Dependent Long-Term Depression in the Mouse Hippocampus.

Spike timing-dependent plasticity (STDP) is a Hebbian learning rule important for synaptic refinement during development and for learning and memory in the adult. Given the importance of the hippocampus in memory, surprisingly little is known about the mechanisms and functions of hippocampal STDP. In the present work, we investigated the requirements for induction of hippocampal spike timing-dependent long-term potentiation (t-LTP) and spike timing-dependent long-term depression (t-LTD) and the mechanisms of these 2 forms of plasticity at CA3-CA1 synapses in young (P12-P18) mouse hippocampus. We found that both t-LTP and t-LTD can be induced at hippocampal CA3-CA1 synapses by pairing presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz). Both t-LTP and t-LTD require NMDA-type glutamate receptors for their induction, but the location and properties of these receptors are different: While t-LTP requires postsynaptic ionotropic NMDA receptor function, t-LTD does not, and whereas t-LTP is blocked by antagonists at GluN2A and GluN2B subunit-containing NMDA receptors, t-LTD is blocked by GluN2C or GluN2D subunit-preferring NMDA receptor antagonists. Both t-LTP and t-LTD require postsynaptic Ca(2+) for their induction. Induction of t-LTD also requires metabotropic glutamate receptor activation, phospholipase C activation, postsynaptic IP3 receptor-mediated Ca(2+) release from internal stores, postsynaptic endocannabinoid (eCB) synthesis, activation of CB1 receptors and astrocytic signaling, possibly via release of the gliotransmitter d-serine. We furthermore found that presynaptic calcineurin is required for t-LTD induction. t-LTD is expressed presynaptically as indicated by fluctuation analysis, paired-pulse ratio, and rate of use-dependent depression of postsynaptic NMDA receptor currents by MK801. The results show that CA3-CA1 synapses display both NMDA receptor-dependent t-LTP and t-LTD during development and identify a presynaptic form of hippocampal t-LTD similar to that previously described at neocortical synapses during development.

Rapamycin restores BDNF-LTP and the persistence of long-term memory in a model of Down's syndrome.

Down's syndrome (DS) is the most prevalent genetic intellectual disability. Memory deficits significantly contribute to the cognitive dysfunction in DS. Previously, we discovered that mTOR-dependent local translation, a pivotal process for some forms of synaptic plasticity, is deregulated in a DS mouse model. Here, we report that these mice exhibit deficits in both synaptic plasticity (i.e., BDNF-long term potentiation) and the persistence of spatial long-term memory. Interestingly, these deficits were fully reversible using rapamycin, a Food and Drug Administration-approved specific mTOR inhibitor; therefore, rapamycin may be a novel pharmacotherapy to improve cognition in DS.

Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aß-dependent expression in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid ß-peptide (Aß) levels. In this study, we investigated the role of presenilin-like signal peptide peptidase-like 2b (SPPL2b) in AD pathophysiology and its potential as a druggable target within the Aß cascade. Exogenous Aß42 influenced SPPL2b expression in human cell lines and acute mouse brain slices. SPPL2b and its AD-related substrate BRI2 were evaluated in the brains of AppNL-G-F knock-in AD mice and human postmortem AD brains. An early high cortical expression of SPPL2b was observed, followed by a downregulation in late AD pathology in AppNL-G-F mice, correlating with synaptic loss. To understand the consequences of pathophysiological SPPL2b dysregulation, we found that SPPL2b overexpression significantly increased APP cleavage, while genetic deletion reduced APP cleavage and Aß production. Notably, postmortem AD brains showed higher levels of SPPL2b's BRI2 substrate compared to healthy control samples. These results strongly support the involvement of SPPL2b in AD pathology. The early Aß-induced upregulation of SPPL2b may enhance Aß production in a vicious cycle, further aggravating Aß pathology. Therefore, SPPL2b emerges as a potential anti-Aß drug target.

Pre-synaptic kainate receptor-mediated facilitation of glutamate release involves PKA and Ca(2+) -calmodulin at thalamocortical synapses.

We have investigated the mechanisms underlying the facilitatory modulation mediated by kainate receptor (KAR) activation in the cortex, using isolated nerve terminals (synaptosomes) and slice preparations. In cortical nerve terminals, kainate (KA, 100 µM) produced an increase in 4-aminopyridine (4-AP)-evoked glutamate release. In thalamocortical slices, KA (1 µM) produced an increase in the amplitude of evoked excitatory post-synaptic currents (eEPSCs) at synapses established between thalamic axon terminals from the ventrobasal nucleus onto stellate neurons of L4 of the somatosensory cortex. In both, synaptosomes and slices, the effect of KA was antagonized by 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted after pre-treatment with a cocktail of antagonists of other receptors whose activation could potentially have produced facilitation of release indirectly. Mechanistically, the observed effects of KA appear to be congruent in synaptosomal and slice preparations. Thus, the facilitation by KA of synaptosomal glutamate release and thalamocortical synaptic transmission were suppressed by the inhibition of protein kinase A and occluded by the stimulation of adenylyl cyclase. Dissecting this G-protein-independent regulation further in thalamocortical slices, the KAR-mediated facilitation of synaptic transmission was found to be sensitive to the block of Ca(2+) permeant KARs by philanthotoxin. Intriguingly, the synaptic facilitation was abrogated by depletion of intracellular Ca(2+) stores by thapsigargin, or inhibition of Ca(2+) -induced Ca(2+) -release by ryanodine. Thus, the KA-mediated modulation was contingent on both Ca(2+) entry through Ca(2+) -permeable KARs and liberation of intracellular Ca(2+) stores. Finally, sensitivity to W-7 indicated that the increased cytosolic [Ca(2+) ] underpinning KAR-mediated regulation of synaptic transmission at thalamocortical synapses, requires downstream activation of calmodulin. We conclude that neocortical pre-synaptic KARs mediate the facilitation of glutamate release and synaptic transmission by a Ca(2+) -calmodulin dependent activation of an adenylyl cyclase/cAMP/protein kinase A signalling cascade, independent of G-protein involvement.

Neuronal and astrocyte determinants of critical periods of plasticity.

Windows of plasticity allow environmental experiences to produce intense activity-dependent changes during postnatal development. The reordering and refinement of neural connections occurs during these periods, significantly influencing the formation of brain circuits and physiological processes in adults. Recent advances have shed light on factors that determine the onset and duration of sensitive and critical periods of plasticity. Although GABAergic inhibition has classically been implicated in closing windows of plasticity, astrocytes and adenosinergic inhibition have also emerged more recently as key determinants of the duration of these periods of plasticity. Here, we review novel aspects of the involvement of GABAergic inhibition, the possible role of presynaptic NMDARs, and the emerging roles of astrocytes and adenosinergic inhibition in determining the duration of windows of plasticity in different brain regions.

Targeting galectin-3 to counteract spike-phase uncoupling of fast-spiking interneurons to gamma oscillations in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists. Neuroinflammation is central to the pathology progression, with evidence suggesting that microglia-released galectin-3 (gal3) plays a pivotal role by amplifying neuroinflammation in AD. However, the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown. METHODS: Here, we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo (20-80 Hz) by performing electrophysiological recordings in the hippocampal CA3 area of wild-type (WT) mice and of the 5×FAD mouse model of AD. In addition, the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes, and amyloid-ß (Aß) plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout (KO). RESULTS: Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner, which was accompanied by impairment of cellular dynamics in fast-spiking interneurons (FSNs) and pyramidal cells. We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139, which also prevented Aß42-induced degradation of gamma oscillations. Furthermore, the 5×FAD mice lacking gal3 (5×FAD-Gal3KO) exhibited WT-like gamma network dynamics and decreased Aß plaque load. CONCLUSIONS: We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs, inducing a network performance collapse. Moreover, our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.

Kainate receptor-mediated depression of glutamatergic transmission involving protein kinase A in the lateral amygdala.

Kainate receptors (KARs) have been described as modulators of synaptic transmission at different synapses. However, this role of KARs has not been well characterized in the amygdala. We have explored the effect of kainate receptor activation at the synapse established between fibers originating at medial geniculate nucleus and the principal cells in the lateral amygdala. We have observed an inhibition of evoked excitatory postsynaptic currents (eEPSCs) amplitude after a brief application of KARs agonists KA and ATPA. Paired-pulse recordings showed a clear pair pulse facilitation that was enhanced after KA or ATPA application. When postsynaptic cells were loaded with BAPTA, the depression of eEPSC amplitude observed after the perfusion of KAR agonists was not prevented. We have also observed that the inhibition of the eEPSCs by KARs agonists was prevented by protein kinase A but not by protein kinase C inhibitors. Taken together our results indicate that KARs present at this synapse are pre-synaptic and their activation mediate the inhibition of glutamate release through a mechanism that involves the activation of protein kinase A.

Presynaptic kainate receptor-mediated facilitation of glutamate release involves Ca2+ -calmodulin at mossy fiber-CA3 synapses.

Presynaptic kainate receptors (KARs) modulate the release of glutamate at synapses established between mossy fibers (MF) and CA3 pyramidal cells in the hippocampus. The activation of KAR by low, nanomolar, kainate concentrations facilitates glutamate release. KAR-mediated facilitation of glutamate release involves the activation of an adenylate cyclase/cyclic adenosine monophosphate/protein kinase A cascade at MF-CA3 synapses. Here, we studied the mechanisms by which KAR activation produces this facilitation of glutamate release in slices and synaptosomes. We find that the facilitation of glutamate release mediated by KAR activation requires an increase in Ca(2+) levels in the cytosol and the formation of a Ca(2+) -calmodulin complex to activate adenylate cyclase. The increase in cytosolic Ca(2+) underpinning this modulation is achieved, both, by Ca(2+) entering via Ca(2+) -permeable KARs and, by the mobilization of intraterminal Ca(2+) stores. Finally, we find that, congruent with the Ca(2+) -calmodulin support of KAR-mediated facilitation of glutamate release, induction of long-term potentiation at MF-CA3 synapses has an obligate requirement for Ca(2+) -calmodulin activity.

S100A9 amyloid growth and S100A9 fibril-induced impairment of gamma oscillations in area CA3 of mouse hippocampus ex vivo is prevented by Bri2 BRICHOS.

The pro-inflammatory and highly amyloidogenic protein S100A9 is central to the amyloid-neuroinflammatory cascade in neurodegenerative diseases leading to cognitive impairment. Molecular chaperone activity of Bri2 BRICHOS has been demonstrated against a range of amyloidogenic polypeptides. Using a combination of thioflavin T fluorescence kinetic assay, atomic force microscopy and immuno electron microscopy we show here that recombinant Bri2 BRICHOS effectively inhibits S100A9 amyloid growth by capping amyloid fibrils. Using ex-vivo neuronal network electrophysiology in mouse brain slices we also show that both native S100A9 and amyloids of S100A9 disrupt cognition-relevant gamma oscillation power and rhythmicity in hippocampal area CA3 in a time- and protein conformation-dependent manner. Both effects were associated with Toll-like receptor 4 (TLR4) activation and were not observed upon TLR4 blockade. Importantly, S100A9 that had co-aggregated with Bri2 BRICHOS did not elicit degradation of gamma oscillations. Taken together, this work provides insights on the potential influence of S100A9 on cognitive dysfunction in Alzheimer's disease (AD) via gamma oscillation impairment from experimentally-induced gamma oscillations, and further highlights Bri2 BRICHOS as a chaperone against detrimental effects of amyloid self-assembly.

Modeling Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes Syndrome Using Patient-Derived Induced Neurons Generated by Direct Reprogramming.

Mitochondrial diseases are a heterogeneous group of rare genetic disorders caused by mutations in nuclear or mitochondrial DNA (mtDNA). These diseases are frequently multisystemic, although mainly affect tissues that require large amounts of energy such as the brain. Mutations in mitochondrial transfer RNA (mt-tRNA) lead to defects in protein translation that may compromise some or all mtDNA-encoded proteins. Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) syndrome is mainly caused by the m.3243A>G mutation in the mt-tRNALeu(UUR) (MT-TL1) gene. Owing to the lack of proper animal models, several cellular models have been developed to study the disease, providing insight in the pathophysiological mechanisms of MELAS. In this study, we show a successful direct conversion of MELAS patient-derived fibroblasts into induced neurons (iNs) for the first time, as well as an electrophysiological characterization of iNs cocultured with astrocytes. In addition, we performed bioenergetics analysis to study the consequences of m.3243A>G mutation in this neuronal model of MELAS syndrome.

Abilities of the BRICHOS domain to prevent neurotoxicity and fibril formation are dependent on a highly conserved Asp residue.

Proteins can self-assemble into amyloid fibrils or amorphous aggregates and thereby cause disease. Molecular chaperones can prevent both these types of protein aggregation, but to what extent the respective mechanisms are overlapping is not fully understood. The BRICHOS domain constitutes a disease-associated chaperone family, with activities against amyloid neurotoxicity, fibril formation, and amorphous protein aggregation. Here, we show that the activities of BRICHOS against amyloid-induced neurotoxicity and fibril formation, respectively, are oppositely dependent on a conserved aspartate residue, while the ability to suppress amorphous protein aggregation is unchanged by Asp to Asn mutations. The Asp is evolutionarily highly conserved in >3000 analysed BRICHOS domains but is replaced by Asn in some BRICHOS families. The conserved Asp in its ionized state promotes structural flexibility and has a pK a value between pH 6.0 and 7.0, suggesting that chaperone effects can be differently affected by physiological pH variations.

Synaptic Plasticity and Oscillations in Alzheimer's Disease: A Complex Picture of a Multifaceted Disease.

Brain plasticity is widely accepted as the core neurophysiological basis of memory and is generally defined by activity-dependent changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). By using diverse induction protocols like high-frequency stimulation (HFS) or spike-timing dependent plasticity (STDP), such crucial cognition-relevant plastic processes are shown to be impaired in Alzheimer's disease (AD). In AD, the severity of the cognitive impairment also correlates with the level of disruption of neuronal network dynamics. Currently under debate, the named amyloid hypothesis points to amyloid-beta peptide 1-42 (Aß42) as the trigger of the functional deviations underlying cognitive impairment in AD. However, there are missing functional mechanistic data that comprehensively dissect the early subtle changes that lead to synaptic dysfunction and subsequent neuronal network collapse in AD. The convergence of the study of both, mechanisms underlying brain plasticity, and neuronal network dynamics, may represent the most efficient approach to address the early triggering and aberrant mechanisms underlying the progressive clinical cognitive impairment in AD. Here we comment on the emerging integrative roles of brain plasticity and network oscillations in AD research and on the future perspectives of research in this field.

Ablation of p75NTR signaling strengthens gamma-theta rhythm interaction and counteracts Aß-induced degradation of neuronal dynamics in mouse hippocampus in vitro.

Gamma and theta brain rhythms play important roles in cognition and their interaction can affect gamma oscillation features. Hippocampal theta oscillations depend on cholinergic and GABAergic input from the medial septum-diagonal band of Broca. These projecting neurons undergo degeneration during aging and maintain high levels of neurotrophin receptor p75 (p75NTR). p75NTR mediates both apoptosis and survival and its expression is increased in Alzheimer's disease (AD) patients. Here, we investigate the importance of p75NTR for the cholinergic input to the hippocampus. Performing extracellular recordings in brain slices from p75NTR knockout mice (p75-/-) in presence of the muscarinic agonist carbachol, we find that gamma oscillation power and rhythmicity are increased compared to wild-type (WT) mice. Furthermore, gamma activity is more phase-locked to the underlying theta rhythm, which renders a stronger coupling of both rhythms. On the cellular level, we find that fast-spiking interneurons (FSNs) fire more synchronized to a preferred gamma phase in p75-/- mice. The excitatory input onto FSN is more rhythmic displaying a higher similarity with the concomitant gamma rhythm. Notably, the ablation of p75NTR counteracts the Aß-induced degradation of gamma oscillations and its nesting within the underlying theta rhythm. Our results show that the lack of p75NTR signaling could promote stronger cholinergic modulation of the hippocampal gamma rhythm, suggesting an involvement of p75NTR in the downregulation of cognition-relevant hippocampal network dynamics in pathologies. Moreover, functional data provided here suggest p75NTR as a suitable target in the search for efficacious treatments to counteract the loss of cognitive function observed in amyloid-driven pathologies such as AD.