-
Frontiers in Aging Neuroscience 2024Studies in rodent models have revealed that oligomeric beta-amyloid protein [Aβ (1-42)] plays an important role in the pathogenesis of Alzheimer's disease. Early...
GluN2A or GluN2B subunits of the NMDA receptor contribute to changes in neuronal excitability and impairments in LTP in the hippocampus of aging mice but do not mediate detrimental effects of oligomeric Aβ (1-42).
Studies in rodent models have revealed that oligomeric beta-amyloid protein [Aβ (1-42)] plays an important role in the pathogenesis of Alzheimer's disease. Early elevations in hippocampal neuronal excitability caused by Aβ (1-42) have been proposed to be mediated via enhanced activation of GluN2B-containing N-methyl-D-aspartate receptors (NMDAR). To what extent GluN2A or GluN2B-containing NMDAR contribute to Aβ (1-42)-mediated impairments of hippocampal function in advanced rodent age is unclear. Here, we assessed hippocampal long-term potentiation (LTP) and neuronal responses 4-5 weeks after bilateral intracerebral inoculation of 8-15 month old GluN2A or GluN2B transgenic mice with oligomeric Aβ (1-42), or control peptide. Whole-cell patch-clamp recordings in CA1 pyramidal neurons revealed a more positive resting membrane potential and increased total spike time in GluN2A, but not GluN2B-hippocampi following treatment with Aβ (1-42) compared to controls. Action potential 20%-width was increased, and the descending slope was reduced, in Aβ-treated GluN2A, but not GluN2B hippocampi. Sag ratio was increased in Aβ-treated GluN2B-mice. Firing frequency was unchanged in wt, GluN2A, and GluN2Bhippocampi after Aβ-treatment. Effects were not significantly different from responses detected under the same conditions in wt littermates, however. LTP that lasted for over 2 h in wt hippocampal slices was significantly reduced in GluN2A and was impaired for 15 min in GluN2B-hippocampi compared to wt littermates. Furthermore, LTP (>2 h) was significantly impaired in Aβ-treated hippocampi of wt littermates compared to wt treated with control peptide. LTP induced in Aβ-treated GluN2A and GluN2B-hippocampi was equivalent to LTP in control peptide-treated transgenic and Aβ-treated wt animals. Taken together, our data indicate that knockdown of GluN2A subunits subtly alters membrane properties of hippocampal neurons and reduces the magnitude of LTP. GluN2B knockdown reduces the early phase of LTP but leaves later phases intact. Aβ (1-42)-treatment slightly exacerbates changes in action potential properties in GluN2A-mice. However, the vulnerability of the aging hippocampus to Aβ-mediated impairments of LTP is not mediated by GluN2A or GluN2B-containing NMDAR.
PubMed: 38832073
DOI: 10.3389/fnagi.2024.1377085 -
Communications Biology Jun 2024Deciphering the functional organization of large biological networks is a major challenge for current mathematical methods. A common approach is to decompose networks...
Deciphering the functional organization of large biological networks is a major challenge for current mathematical methods. A common approach is to decompose networks into largely independent functional modules, but inferring these modules and their organization from network activity is difficult, given the uncertainties and incompleteness of measurements. Typically, some parts of the overall functional organization, such as intermediate processing steps, are latent. We show that the hidden structure can be determined from the statistical moments of observable network components alone, as long as the functional relevance of the network components lies in their mean values and the mean of each latent variable maps onto a scaled expectation of a binary variable. Whether the function of biological networks permits a hierarchical modularization can be falsified by a correlation-based statistical test that we derive. We apply the test to gene regulatory networks, dendrites of pyramidal neurons, and networks of spiking neurons.
Topics: Gene Regulatory Networks; Humans; Animals; Pyramidal Cells
PubMed: 38831002
DOI: 10.1038/s42003-024-06342-y -
Developmental Neuroscience Jun 2024Developmental windows in which experiences can elicit long-lasting effects on brain circuitry and behavior are called 'sensitive periods' and reflect a state of...
INTRODUCTION
Developmental windows in which experiences can elicit long-lasting effects on brain circuitry and behavior are called 'sensitive periods' and reflect a state of heightened plasticity. The classic example of a sensitive period comes from studies of sensory systems, like the visual system, where early visual experience is required for normal wiring of primary visual cortex and proper visual functioning. At a mechanistic level, loss of incoming visual input results in a decrease in activity in thalamocortical neurons representing the affected eye, resulting in an activity-dependent reduction in the representation of those inputs in the visual cortex and loss of visual perception in that eye. While associative cortical regions like the medial prefrontal cortex (mPFC) do not receive direct sensory input, recent findings demonstrate that changes in activity levels experienced by this region during defined windows in early development may also result in long-lasting changes in prefrontal cortical circuitry, network function and behavior. For example, we recently demonstrated that decreasing the activity of mPFC parvalbumin-expressing (PV) interneurons during a period of time encompassing peripuberty (postnatal day P14) to adolescence (P50) led to a long-lasting decrease in their functional inhibition of pyramidal cells, as well as impairments in cognitive flexibility. While the effects of manipulating mPFC PV interneuron activity were selective to development, and not adulthood, the exact timing of the sensitive period for this manipulation remains unknown.
METHODS
To refine the sensitive period in which inhibiting mPFC PV cell activity can lead to persist effects on prefrontal functioning we used a chemogenetic approach to restrict our inhibition of mPFC PV activity to two distinct windows: 1) peripuberty (P14-P32) and 2) early adolescence (P33-P50). We then investigated adult behavior after P90. In parallel, we performed histological analysis of molecular markers associated with sensitive period onset and offset in visual cortex, to define the onset and offset of peak sensitive period plasticity in the mPFC.
RESULTS
We found that inhibition of mPFC PV interneurons in peripuberty (P14-P32), but not adolescence (P33-P50), led to an impairment in set shifting behavior in adulthood manifest as an increase in trials to reach criterion performance and errors. Consistent with a pubertal onset of sensitive period plasticity in the PFC, we found histological markers of sensitive period onset and offset also demarcated P14 and P35, respectively. The time course of expression of these markers was similar in visual cortex.
CONCLUSION
Both lines of research converge on the peripubertal period (P14-32) as one of heightened sensitive period plasticity in the mPFC. Further, our direct comparison of markers of sensitive period plasticity across the prefrontal and visual cortex suggests a similar time course of expression, challenging the notion that sensitive periods occur hierarchically. Together, these findings extend our knowledge about the nature and timing of sensitive period plasticity in the developing mPFC.
PubMed: 38830346
DOI: 10.1159/000539584 -
Proceedings of the National Academy of... Jun 2024Even a transient period of hearing loss during the developmental critical period can induce long-lasting deficits in temporal and spectral perception. These perceptual...
Even a transient period of hearing loss during the developmental critical period can induce long-lasting deficits in temporal and spectral perception. These perceptual deficits correlate with speech perception in humans. In gerbils, these hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABA and metabotropic GABA receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABA receptors. Therefore, we developed viral vectors to express proteins that would upregulate gerbil postsynaptic inhibitory receptor subunits (GABA, ; GABA, ) in pyramidal neurons, and an enzyme that mediates GABA synthesis () presynaptically in parvalbumin-expressing interneurons. A transient period of developmental hearing loss during the auditory critical period significantly impaired perceptual performance on two auditory tasks: amplitude modulation depth detection and spectral modulation depth detection. We then tested the capacity of each vector to restore perceptual performance on these auditory tasks. While both GABA receptor vectors increased the amplitude of cortical inhibitory postsynaptic potentials, only viral expression of postsynaptic GABA receptors improved perceptual thresholds to control levels. Similarly, presynaptic GAD65 expression improved perceptual performance on spectral modulation detection. These findings suggest that recovering performance on auditory perceptual tasks depends on GABA receptor-dependent transmission at the auditory cortex parvalbumin to pyramidal synapse and point to potential therapeutic targets for developmental sensory disorders.
Topics: Animals; Auditory Cortex; Gerbillinae; Hearing Loss; Receptors, GABA-B; Glutamate Decarboxylase; Receptors, GABA-A; Parvalbumins; Auditory Perception; Pyramidal Cells; Genetic Vectors
PubMed: 38830095
DOI: 10.1073/pnas.2311570121 -
Cognitive Neurodynamics Jun 2024An epileptic seizure can usually be divided into three stages: interictal, preictal, and ictal. However, the seizure underlying the transition from interictal to ictal...
UNLABELLED
An epileptic seizure can usually be divided into three stages: interictal, preictal, and ictal. However, the seizure underlying the transition from interictal to ictal activities in the brain involves complex interactions between inhibition and excitation in groups of neurons. To explore this mechanism at the level of a single population, this paper employed a neural mass model, named the complete physiology-based model (cPBM), to reconstruct electroencephalographic (EEG) signals and to infer the changes in excitatory/inhibitory connections related to excitation-inhibition (E-I) balance based on an open dataset recorded for ten epileptic patients. Since epileptic signals display spectral characteristics, spectral dynamic causal modelling (DCM) was applied to quantify these frequency characteristics by maximizing the free energy in the framework of power spectral density (PSD) and estimating the cPBM parameters. In addition, to address the local maximum problem that DCM may suffer from, a hybrid deterministic DCM (H-DCM) approach was proposed, with a deterministic annealing-based scheme applied in two directions. The H-DCM approach adjusts the temperature introduced in the objective function by gradually decreasing the temperature to obtain relatively good initialization and then gradually increasing the temperature to search for a better estimation after each maximization. The results showed that (i) reconstructed EEG signals belonging to the three stages together with their PSDs can be reproduced from the estimated parameters of the cPBM; (ii) compared to DCM, traditional D-DCM and anti D-DCM, the proposed H-DCM shows higher free energies and lower root mean square error (RMSE), and it provides the best performance for all stages (e.g., the RMSEs between the reconstructed PSD computed from the reconstructed EEG signal and the sample PSD obtained from the real EEG signal are 0.33 ± 0.08, 0.67 ± 0.37 and 0.78 ± 0.57 in the interictal, preictal and ictal stages, respectively); and (iii) the transition from interictal to ictal activity can be explained by an increase in the connections between pyramidal cells and excitatory interneurons and between pyramidal cells and fast inhibitory interneurons, as well as a decrease in the self-loop connection of the fast inhibitory interneurons in the cPBM. Moreover, the E-I balance, defined as the ratio between the excitatory connection from pyramidal cells to fast inhibitory interneurons and the inhibitory connection with the self-loop of fast inhibitory interneurons, is also significantly increased during the epileptic seizure transition.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s11571-023-09976-6.
PubMed: 38826671
DOI: 10.1007/s11571-023-09976-6 -
Experimental & Molecular Medicine Jun 2024Cortical neuromodulation (CNM) is widely used to promote recovery after stroke. Despite the beneficial results of CNM, the roles played by different neuron types in the...
Cortical neuromodulation (CNM) is widely used to promote recovery after stroke. Despite the beneficial results of CNM, the roles played by different neuron types in the effects of current CNM techniques are unable to be differentiated. Our aim was to use selective optogenetic cortical stimulation to explore how different subpopulations of neuronal cells contribute to poststroke recovery. We transduced the sensory-parietal cortex (SPC) of rats with CamKII-ChR2 (pyramidal neurons), PV-ChR2 (parvalbumin-expressing inhibitory neurons), or hSyn-ChR2 (pan-neuronal population) before inducing photothrombotic capsular infarct lesions. We found that selective stimulation of inhibitory neurons resulted in significantly greater motor recovery than stimulation of excitatory neurons or the pan-neuronal population. Furthermore, 2-deoxy-2-[F] fluoro-D-glucose microPET (FDG-microPET) imaging revealed a significant reduction in cortical diaschisis and activation of the corticostriatal neural circuit, which were correlated with behavioral recovery in the PV-ChR2 group. The spatial pattern of brain-derived neurotrophic factor (BDNF) expression was evident in the stimulated cortex and underlying cortico-subcortical circuit. Our results indicate that the plasticity of inhibitory neurons is crucial for functional recovery after capsular infarct. Modifying CNM parameters to potentiate the stimulation of inhibitory neurons could improve poststroke outcomes.
PubMed: 38825647
DOI: 10.1038/s12276-024-01253-8 -
Schizophrenia Bulletin Jun 2024Schizophrenia (SCZ) is a serious mental illness with complex pathology, including abnormalities in the glutamate system. Glutamate is rapidly removed from the synapse by...
BACKGROUND
Schizophrenia (SCZ) is a serious mental illness with complex pathology, including abnormalities in the glutamate system. Glutamate is rapidly removed from the synapse by excitatory amino acid transporters (EAATs). Changes in the expression and localization of the primary glutamate transporter EAAT2 are found in the brain in central nervous system (CNS) disorders including SCZ. We hypothesize that neuronal expression and function of EAAT2 are increased in the frontal cortex in subjects diagnosed with SCZ.
STUDY DESIGN
EAAT2 protein expression and glutamate transporter function were assayed in synaptosome preparations from the dorsolateral prefrontal cortex (DLPFC) of SCZ subjects and age- and sex-matched nonpsychiatrically ill controls. EAAT2 splice variant transcript expression was assayed in enriched populations of neurons and astrocytes from the DLPFC. Pathway analysis of publicly available transcriptomic datasets was carried out to identify biological changes associated with EAAT2 perturbation in different cell types.
RESULTS
We found no significant changes in EAAT2 protein expression or glutamate uptake in the DLPFC in SCZ subjects compared with controls (n = 10/group). Transcript expression of EAAT2 and signaling molecules associated with EAAT2b trafficking (CaMKIIa and DLG1) were significantly altered in enriched populations of astrocytes and pyramidal neurons (P < .05) in SCZ (n = 16/group). These changes were not associated with antipsychotic medications. Pathway analysis also identified cell-type-specific enrichment of biological pathways associated with perturbation of astrocyte (immune pathways) and neuronal (metabolic pathways) EAAT2 expression.
CONCLUSIONS
Overall, these data support the growing body of evidence for the role of dysregulation of the glutamate system in the pathophysiology of SCZ.
PubMed: 38825587
DOI: 10.1093/schbul/sbae092 -
Molecular Pharmacology May 2024Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical...
Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin (5-HT) receptor antagonists, such as quetiapine and olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carbamazepine, and valproate, show therapeutic synergy and are often prescribed in combination for the treatment of bipolar disorder. Combination therapy is a complex task for clinicians and patients, often resulting in unexpected difficulties with dosing, drug tolerances, and decreased patient compliance. Thus, an unmet need for bipolar disorder treatment is to develop a therapeutic agent that targets both 5-HT receptors and VGSCs. Towards this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT receptors and blocks sodium current. The new compound, -(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, G-mediated, calcium flux at 5-HT receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT, 5-HT, and 5-HT receptors. At similar concentrations, XOB administration inhibits sodium current in heterologous cells and results in reduced action potential (AP) firing and VGSC-related AP properties in mouse prefrontal cortex layer V pyramidal neurons. Thus, XOB represents a new, proof-of-principle tool that can be used for future preclinical investigations and therapeutic development. This polypharmacology approach of developing a single molecule to act upon two targets, which are currently independently targeted by combination therapies, may lead to safer alternatives for the treatment of psychiatric disorders that are increasingly being found to benefit from the simultaneous targeting of multiple receptors. We synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT receptors and voltage-gated sodium channels (VGSCs), in heterologous cells, and inhibits the intrinsic excitability of mouse prefrontal cortex layer V pyramidal neurons in brain slices. XOB represents a valuable new proof-of-principle tool for future preclinical investigations and provides a novel molecular approach to the pharmacological treatment of complex neuropsychiatric disease, which often requires a combination of therapeutics for sufficient patient benefit.
PubMed: 38821630
DOI: 10.1124/molpharm.123.000837 -
Brain Research May 2024Damage to the hippocampus leads to increased anxiety, memory problems, and learning disabilities. Melatonin (MLT), a hormone secreted by the pineal gland, serves as an...
Exploring the impact of melatonin and omega-3, individually and in combination, on cognitive function, histological changes, and oxidant-antioxidant balance in male rats with dorsal CA1 hippocampal lesions.
BACKGROUND AND OBJECTIVE
Damage to the hippocampus leads to increased anxiety, memory problems, and learning disabilities. Melatonin (MLT), a hormone secreted by the pineal gland, serves as an antioxidant and provides defense against nerve damage. Omega-3 (ω3) is known for improving brain function. This study aims to examine the impact of melatonin and omega-3, both individually and in combination, on cognitive function, histological changes, and the balance between oxidants and antioxidants in male rats with injuries to the dorsal CA1 hippocampus.
MATERIAL AND METHODS
Five rat groups (n = 8) were examined. The sham group was given normal saline via intraperitoneal (ip) and gavage routes. After a local lesion in the hippocampus, the lesion group underwent the same treatment. The MLT group was given melatonin (10 mg/kg, ip), the ω3 group was provided with omega-3 (0.8 g/kg, gavage), and the MLT + ω3 group received both treatments. Injections were administered every other day for 10 days. On the 11th day, behavioral assessments were conducted, and then pyramidal cells were quantified using image analysis software. Serum samples were assessed for levels of oxidants and antioxidants.
RESULTS
The results from the open field test indicated a significant increase in distance moved in the Lesion + MLT + ω3 group compared to the lesion group (P < 0.05). Performance in the novel object recognition test showed improvement in the ω3 and MLT + ω3 treated groups compared to the lesion group (P < 0.05). Additionally, social interaction duration notably increased in the ω3, MLT, and MLT + ω3 treated groups compared to the lesion group. The number of degenerated cells in the CA1, CA2, and CA3 areas of the lesion group significantly increased compared to the sham group, but melatonin and omega-3 notably reduced this number (P < 0.05). The serum levels of the antioxidant enzymes,include superoxide dismutase, glutathione peroxidase, and catalase in the lesion group notably changed compared to the sham group, but omega-3 effectively restored them to control levels.
CONCLUSION
According to increase in distance moved, memory function, learning and social interactions of the animal in the behavioral results and the reduction of degenerate cells in the histological results, it can be said that these effects may be part of the neuroprotective effects of melatonin and omega-3. The increase in levels of antioxidant enzymes, particularly omega-3, indicates their promise as therapeutic agents for reducing oxidative stress-induced damage in neurological disorders.
PubMed: 38821333
DOI: 10.1016/j.brainres.2024.149046 -
Frontiers in Cellular Neuroscience 2024Intracellular Ca-signaling in astrocytes is instrumental for their brain "housekeeping" role and astroglial control of synaptic plasticity. An important source for...
Intracellular Ca-signaling in astrocytes is instrumental for their brain "housekeeping" role and astroglial control of synaptic plasticity. An important source for elevating the cytosolic Ca level in astrocytes is a release from endoplasmic reticulum which can be triggered via two fundamental pathways: IP3 receptors and calcium-induced calcium release (CICR) mediated by Ca-sensitive ryanodine receptors (RyRs). While the physiological role for glial IP3 became a focus of intensive research and debate, ryanodine receptors received much less attention. We explored the role for ryanodine receptors in the modulation of cytosolic Ca-signaling in the cortical and hippocampal astrocytes, astrocyte-neuron communication and astroglia modulation of synaptic plasticity. Our data show that RyR-mediated Ca-induced Ca-release from ER brings substantial contribution into signaling in the functional microdomains hippocampal and neocortical astrocytes. Furthermore, RyR-mediated CICR activated the release of ATP and glutamate from hippocampal and neocortical astrocytes which, in turn, elicited transient purinergic and tonic glutamatergic currents in the neighboring pyramidal neurons. The CICR-facilitated release of ATP and glutamate was inhibited after intracellular perfusion of astrocytes with ryanodine and BAPTA and in the transgenic dnSNARE mice with impaired astroglial exocytosis. We also found out that RyR-mediated amplification of astrocytic Ca-signaling enhanced the long-term synaptic potentiation in the hippocampus and neocortex of aged mice. Combined, our data demonstrate that ryanodine receptors are essential for astrocytic Ca-signaling and efficient astrocyte-neuron communications. The RyR-mediated CICR contributes to astrocytic control of synaptic plasticity and can underlie, at least partially, neuroprotective and cognitive effects of caffein.
PubMed: 38812795
DOI: 10.3389/fncel.2024.1382010