Regulation Of Neuronal Activity Research Articles

Enhanced transport of brain interstitial solutes mediated by stimulation of sensorimotor area in rats.

Solute transport in the brain is essential for maintaining cerebral homeostasis. Recent studies have shown that neuronal activity enhances the transport of cerebrospinal fluid solutes, but its impact on interstitial solute transport has not been established. In this study, we investigated whether neuronal activity affects the transport of interstitial solutes. Fluorescent Texas Red ovalbumin was injected intracortically into the unilateral sensorimotor area of the Sprague-Dawley rats. Regional neuronal activity around the injection site was elicited by transdermal electrical stimulation of a corresponding forelimb for 90 min (n = 6). The control group of rats (n = 6) did not receive any electrical stimulation. Subsequently, the spatial distributions of the tracer over the cortical surface and from the brain sections were imaged and compared between two groups. The ovalbumin fluorescence from the cervical lymph nodes was also compared between the groups to evaluate the effect of neuronal activity on solute clearance from the brain. Tracer distribution over the brain surface/sections revealed a significantly higher uptake of ovalbumin in the hemisphere ipsilateral to the injection among the stimulated animals compared to the unstimulated group. This difference, however, was not seen in the hemisphere contralateral to injection. A trace amount of ovalbumin in the lymph nodes was equivalent between the groups, which indicated a considerable time needed for interstitial solutes to be drained from the brain. The results suggest that neuronal activity enhances interstitial solute transport, calling for further examination of ultimate routes and mechanisms for brain solute clearance.

Soft Bioelectronics Using Nanomaterials and Nanostructures for Neuroengineering.

The identification of neural networks for large areas and the regulation of neuronal activity at the single-neuron scale have garnered considerable attention in neuroscience. In addition, detecting biochemical molecules and electrically, optically, and chemically controlling neural functions are key research issues. However, conventional rigid and bulky bioelectronics face challenges for neural applications, including mechanical mismatch, unsatisfactory signal-to-noise ratio, and poor integration of multifunctional components, thereby degrading the sensing and modulation performance, long-term stability and biocompatibility, and diagnosis and therapy efficacy. Implantable bioelectronics have been developed to be mechanically compatible with the brain environment by adopting advanced geometric designs and utilizing intrinsically stretchable materials, but such advances have not been able to address all of the aforementioned challenges.Recently, the exploration of nanomaterial synthesis and nanoscale fabrication strategies has facilitated the design of unconventional soft bioelectronics with mechanical properties similar to those of neural tissues and submicrometer-scale resolution comparable to typical neuron sizes. The introduction of nanotechnology has provided bioelectronics with improved spatial resolution, selectivity, single neuron targeting, and even multifunctionality. As a result, this state-of-the-art nanotechnology has been integrated with bioelectronics in two main types, i.e., bioelectronics integrated with synthesized nanomaterials and bioelectronics with nanoscale structures. The functional nanomaterials can be synthesized and assembled to compose bioelectronics, allowing easy customization of their functionality to meet specific requirements. The unique nanoscale structures implemented with the bioelectronics could maximize the performance in terms of sensing and stimulation. Such soft nanobioelectronics have demonstrated their applicability for neuronal recording and modulation over a long period at the intracellular level and incorporation of multiple functions, such as electrical, optical, and chemical sensing and stimulation functions.In this Account, we will discuss the technical pathways in soft bioelectronics integrated with nanomaterials and implementing nanostructures for application to neuroengineering. We traced the historical development of bioelectronics from rigid and bulky structures to soft and deformable devices to conform to neuroengineering requirements. Recent approaches that introduced nanotechnology into neural devices enhanced the spatiotemporal resolution and endowed various device functions. These soft nanobioelectronic technologies are discussed in two categories: bioelectronics with synthesized nanomaterials and bioelectronics with nanoscale structures. We describe nanomaterial-integrated soft bioelectronics exhibiting various functionalities and modalities depending on the integrated nanomaterials. Meanwhile, soft bioelectronics with nanoscale structures are explained with their superior resolution and unique administration methods. We also exemplified the neural sensing and stimulation applications of soft nanobioelectronics across various modalities, showcasing their clinical applications in the treatment of neurological diseases, such as brain tumors, epilepsy, and Parkinson's disease. Finally, we discussed the challenges and direction of next-generation technologies.

WNK-SPAK-NKCC1-KCC2 pathway in SCN: a novel regulator of neuronal activity

Background: The suprachiasmatic nucleus (SCN) plays a vital role in regulating an organism's physiological and behavioral processes by synchronizing them with the light-dark cycle. The SCN receives GABAergic inputs that may be excitatory or inhibitory, depending on the intracellular chloride concentration ([Cl−]i) that is regulated by NKCC1 and KCC2 cotransporters, determined by the WNK-SPAK/OSR1 phosphorylation pathway. Our study aimed to investigate the role of the WNK-SPAK-NKCC1-KCC pathway in regulating SCN neuronal activity.Methods: First, we perform an in silico analysis to determine the expression of the genes involved in this pathway. Furthermore, the expression of the proteins was confirmed by an immunofluorescence assay. Next, to determine if the WNK-SPAK-NKCC1-KCC2 pathway affects neuronal activity in the SCN we performed the immunohistochemical analysis of c-Fos expression in the SCN at ZT2 and ZT14 in the SPAK-KI mice. Finally, to find out if the change in SCN neuronal activity between day and night is related to pathway activity, we performed an immunofluorescence study. Results: We observed that various genes governing the pathway's regulation exhibit oscillations not only in neurons but also in other cell types. Remarkably, SPAK-KI mice displayed a significant surge in neuronal activity at ZT2 when contrasted with the control group. Additionally, we detected increased phosphorylation levels of WNK, SPAK, NKCC1, and KCC2 isoforms at ZT14 as compared to ZT2.Conclusions: Our study highlights the role of SPAK kinase in regulating SCN neuronal activity and suggests that the pathway is active during the dark period, leading to an increase in [Cl−]i during the day, as previously reported. The authors are supported by grants from CONACyT Mexico no. 87794, and from PAPIIT UNAM no IA208522 and IN223324. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Functional Analyses of Four Cryptochromes From Aquatic Organisms After Heterologous Expression in Drosophila melanogaster Circadian Clock Cells.

Cryptochromes (Crys) represent a multi-facetted class of proteins closely associated with circadian clocks. They have been shown to function as photoreceptors but also to fulfill light-independent roles as transcriptional repressors within the negative feedback loop of the circadian clock. In addition, there is evidence for Crys being involved in light-dependent magneto-sensing, and regulation of neuronal activity in insects, adding to the functional diversity of this cryptic protein class. In mammals, Crys are essential components of the circadian clock, but their role in other vertebrates is less clear. In invertebrates, Crys can function as circadian photoreceptors, or as components of the circadian clock, while in some species, both light-receptive and clock factor roles coexist. In the current study, we investigate the function of Cry proteins in zebrafish (Danio rerio), a freshwater teleost expressing 6 cry genes. Zebrafish peripheral circadian clocks are intrinsically light-sensitive, suggesting the involvement of Cry in light-resetting. Echinoderms (Strongylocentrotus purpuratus) represent the only class of deuterostomes that possess an orthologue (SpuCry) of the light-sensitive Drosophila melanogaster Cry, which is an important component of the light-resetting pathway, but also works as transcriptional repressor in peripheral clocks of fruit flies. We therefore investigated the potential of different zebrafish cry genes and SpuCry to replace the light-resetting and repressor functions of Drosophila Cry by expressing them in fruit flies lacking endogenous cry function. Using various behavioral and molecular approaches, we show that most Cry proteins analyzed are able to fulfill circadian repressor functions in flies, except for one of the zebrafish Crys, encoded by cry4a. Cry4a also shows a tendency to support light-dependent Cry functions, indicating that it might act in the light-input pathway of zebrafish.

Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons

Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of invitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.

Three‐Photon Infrared Stimulation of Endogenous Neuroreceptors in Vivo

AbstractTo interrogate neural circuits and crack their codes, in vivo brain activity imaging must be combined with spatiotemporally precise stimulation in three dimensions using genetic or pharmacological specificity. This challenge requires deep penetration and focusing as provided by infrared light and multiphoton excitation, and has promoted two‐photon photopharmacology and optogenetics. However, three‐photon brain stimulation in vivo remains to be demonstrated. We report the regulation of neuronal activity in zebrafish larvae by three‐photon excitation of a photoswitchable muscarinic agonist at 50 pM, a billion‐fold lower concentration than used for uncaging, and with mid‐infrared light of 1560 nm, the longest reported photoswitch wavelength. Robust, physiologically relevant photoresponses allow modulating brain activity in wild‐type animals with spatiotemporal and pharmacological precision. Computational calculations predict that azobenzene‐based ligands have high three‐photon absorption cross‐section and can be used directly with pulsed infrared light. The expansion of three‐photon pharmacology will deeply impact basic neurobiology and neuromodulation phototherapies.

Three-Photon Infrared Stimulation of Endogenous Neuroreceptors in Vivo.

To interrogate neural circuits and crack their codes, in vivo brain activity imaging must be combined with spatiotemporally precise stimulation in three dimensions using genetic or pharmacological specificity. This challenge requires deep penetration and focusing as provided by infrared light and multiphoton excitation, and has promoted two-photon photopharmacology and optogenetics. However, three-photon brain stimulation in vivo remains to be demonstrated. We report the regulation of neuronal activity in zebrafish larvae by three-photon excitation of a photoswitchable muscarinic agonist at 50 pM, a billion-fold lower concentration than used for uncaging, and with mid-infrared light of 1560 nm, the longest reported photoswitch wavelength. Robust, physiologically relevant photoresponses allow modulating brain activity in wild-type animals with spatiotemporal and pharmacological precision. Computational calculations predict that azobenzene-based ligands have high three-photon absorption cross-section and can be used directly with pulsed infrared light. The expansion of three-photon pharmacology will deeply impact basic neurobiology and neuromodulation phototherapies.

The Role of Perineuronal Nets in the Contralateral Hemisphere in the Electroacupuncture-Mediated Rehabilitation of Poststroke Dysphagia Mice.

Acupuncture at Lianquan (CV23) acupoint has been shown to improve swallowing function in poststroke dysphagia (PSD). This improvement is supposed to be associated with the regulation of neuronal activity in the contralateral primary motor cortex (M1), while the underlying mechanism still needs to be elucidated. Perineuronal nets (PNNs) are well-known to be involved in the regulation of neuronal activity. Thus, we here aimed to detect the role of PNNs in the contralateral M1 hemisphere in the electroacupuncture (EA)-mediated effect in male mice. The results were obtained from a combination of methods, including in vitro slice electrophysiological recording, in vivo electrophysiological recording, and immunofluorescent staining in male mice. These results showed a decrease of the excitatory postsynaptic currents (sEPSCs) and no alteration of the inhibitory postsynaptic currents (sIPSCs) in the GABAergic neurons and the tonic inhibition in the excitatory neurons in the contralateral M1 after stroke induction, and EA recovered the impaired sEPSCs in the GABAergic neurons. We further found that the effect of EA-induced increase of c-Fos expression, enhancement of spike firing, potentiation of sEPSCs in the excitatory neurons, and improvement of swallowing function were all blocked by the removal of PNNs in the contralateral M1. In conclusion, the PNNs in the contralateral M1 was suggested to be participated in stroke pathogenesis and might be associated with the EA-mediated swallowing function rehabilitation of PSD in male mice. Our study provides insight into how PNNs might be involved in the mechanism of EA treatment for stroke rehabilitation.

Critical-like Brain Dynamics in a Continuum from Second- to First-Order Phase Transition.

The classic brain criticality hypothesis postulates that the brain benefits from operating near a continuous second-order phase transition. Slow feedback regulation of neuronal activity could, however, lead to a discontinuous first-order transition and thereby bistable activity. Observations of bistability in awake brain activity have nonetheless remained scarce and its functional significance unclear. Moreover, there is no empirical evidence to support the hypothesis that the human brain could flexibly operate near either a first- or second-order phase transition despite such a continuum being common in models. Here, using computational modeling, we found bistable synchronization dynamics to emerge through elevated positive feedback and occur exclusively in a regimen of critical-like dynamics. We then assessed bistability in vivo with resting-state MEG in healthy adults (7 females, 11 males) and stereo-electroencephalography in epilepsy patients (28 females, 36 males). This analysis revealed that a large fraction of the neocortices exhibited varying degrees of bistability in neuronal oscillations from 3 to 200 Hz. In line with our modeling results, the neuronal bistability was positively correlated with classic assessment of brain criticality across narrow-band frequencies. Excessive bistability was predictive of epileptic pathophysiology in the patients, whereas moderate bistability was positively correlated with task performance in the healthy subjects. These empirical findings thus reveal the human brain as a one-of-a-kind complex system that exhibits critical-like dynamics in a continuum between continuous and discontinuous phase transitions.SIGNIFICANCE STATEMENT In the model, while synchrony per se was controlled by connectivity, increasing positive local feedback led to gradually emerging bistable synchrony with scale-free dynamics, suggesting a continuum between second- and first-order phase transitions in synchrony dynamics inside a critical-like regimen. In resting-state MEG and SEEG, bistability of ongoing neuronal oscillations was pervasive across brain areas and frequency bands and was observed only with concurring critical-like dynamics as the modeling predicted. As evidence for functional relevance, moderate bistability was positively correlated with executive functioning in the healthy subjects, and excessive bistability was associated with epileptic pathophysiology. These findings show that critical-like neuronal dynamics in vivo involves both continuous and discontinuous phase transitions in a frequency-, neuroanatomy-, and state-dependent manner.

Cerebrospinal fluid solute transport associated with sensorimotor brain activity in rodents

Cerebrospinal fluid (CSF) is crucial for maintaining neuronal homeostasis, providing nutrition, and removing metabolic waste from the brain. However, the relationship between neuronal activity and CSF solute transport remains poorly understood. To investigate the effect of regional neuronal activity on CSF solute transport, Sprague–Dawley rats (all male, n = 30) under anesthesia received an intracisternal injection of a fluorescent tracer (Texas Red ovalbumin) and were subjected to unilateral electrical stimulation of a forelimb. Two groups (n = 10 each) underwent two different types of stimulation protocols for 90 min, one including intermittent 7.5-s resting periods and the other without rest. The control group was not stimulated. Compared to the control, the stimulation without resting periods led to increased transport across most of the cortical areas, including the ventricles. The group that received intermittent stimulation showed an elevated level of solute uptake in limited areas, i.e., near/within the ventricles and on the ventral brain surface. Interhemispheric differences in CSF solute transport were also found in the cortical regions that overlap with the forelimb sensorimotor area. These findings suggest that neuronal activity may trigger local and brain-wide increases in CSF solute transport, contributing to waste clearance.

Amplitude of Low-Frequency Fluctuation to Determine Disturbed Spontaneous Brain-Activity Pattern in Patients with Diabetic Optic Neuropathy.

This study aimed to explore the spontaneous brain activity in patients with diabetic optic neuropathy (DON) by using the amplitude of low-frequency fluctuation (ALFF) technique. Sixteen DON patients and 16 age- and sex-matched healthy controls (HCs) were recruited. ALFF along with functional MRI method was used to detect the intrinsic brain activity alterations. The mean values of ALFF in DON patients and HCs were analyzed by receiver operating characteristic (ROC) curves. Pearson's correlation analysis was used to determine the correlation between Hospital Anxiety and Depression Scale (HADS) and ALFF values of DONs. The DON group showed significantly increased ALFF values in the fusiform gyrus, and decreased ALFF values in the medial frontal gyrus/left frontal superior orbit/right frontal medial orbit, and left frontal inferior triangle. ROC curve analysis indicated that the accuracy of AUC was good. The anxiety scale and depression scale of the DON group were negatively correlated with the ALFF values of the medial frontal gyrus. DON is a neurodegenerative disease involving multiple brain regions. The abnormal activity of neurons in these brain regions helps to reveal the underlying neural mechanisms of brain activity related to DON.

Quantification of prefrontal cortical neuronal ensembles following conditioned fear learning in a Fos-LacZ transgenic rat with photoacoustic imaging in Vivo

Understanding the neurobiology of complex behaviors requires measurement of activity in the discrete population of active neurons, neuronal ensembles, which control the behavior. Conventional neuroimaging techniques ineffectively measure neuronal ensemble activity in the brain in vivo because they assess the average regional neuronal activity instead of the specific activity of the neuronal ensemble that mediates the behavior. Our functional molecular photoacoustic tomography (FM-PAT) system allows direct imaging of Fos-dependent neuronal ensemble activation in Fos-LacZ transgenic rats in vivo. We tested four experimental conditions and found increased FM-PAT signal in prefrontal cortical areas in rats undergoing conditioned fear or novel context exposure. A parallel immunofluorescence ex vivo study of Fos expression found similar findings. These findings demonstrate the ability of FM-PAT to measure Fos-expressing neuronal ensembles directly in vivo and support a mechanistic role for the prefrontal cortex in higher-order processing of response to specific stimuli or environmental cues.

Temporal scaling of dopamine neuron firing and dopamine release by distinct ion channels shape behavior.

Dopamine is broadly implicated in reinforcement learning, but how patterns of dopamine activity are generated is poorly resolved. Here, we demonstrate that two ion channels, Kv4.3 and BKCa1.1, regulate the pattern of dopamine neuron firing and dopamine release on different time scales to influence separate phases of reinforced behavior in mice. Inactivation of Kv4.3 in VTA dopamine neurons increases ex vivo pacemaker activity and excitability that is associated with increased in vivo firing rate and ramping dynamics before lever press in a learned instrumental paradigm. Loss of Kv4.3 enhances performance of the learned response and facilitates extinction. In contrast, loss of BKCa1.1 increases burst firing and phasic dopamine release that enhances learning of an instrumental response and enhances extinction burst lever pressing in early extinction that is associated with a greater change in activity between reinforced and unreinforced actions. These data demonstrate that disruption of intrinsic regulators of neuronal activity differentially affects dopamine dynamics during reinforcement and extinction learning.

Neuronal activity and remyelination: new insights into the molecular mechanisms and therapeutic advancements.

This article reviews the role of neuronal activity in myelin regeneration and the related neural signaling pathways. The article points out that neuronal activity can stimulate the formation and regeneration of myelin, significantly improve its conduction speed and neural signal processing ability, maintain axonal integrity, and support axonal nutrition. However, myelin damage is common in various clinical diseases such as multiple sclerosis, stroke, dementia, and schizophrenia. Although myelin regeneration exists in these diseases, it is often incomplete and cannot promote functional recovery. Therefore, seeking other ways to improve myelin regeneration in clinical trials in recent years is of great significance. Research has shown that controlling neuronal excitability may become a new intervention method for the clinical treatment of demyelinating diseases. The article discusses the latest research progress of neuronal activity on myelin regeneration, including direct or indirect stimulation methods, and the related neural signaling pathways, including glutamatergic, GABAergic, cholinergic, histaminergic, purinergic and voltage-gated ion channel signaling pathways, revealing that seeking treatment strategies to promote myelin regeneration through precise regulation of neuronal activity has broad prospects.

The Role of Selenium and Manganese in the Formation, Diagnosis and Treatment of Cervical, Endometrial and Ovarian Cancer.

Selenium (Se) and manganese (Mn) are essential micronutrients that are important elements of cell metabolism. They are involved in the composition of enzyme systems and regulate enzyme activity. Disturbances in the homeostasis of these micronutrients affect the development of many diseases and carcinogenesis, which can be linked to increased levels of oxidative stress and impaired antioxidant properties of many enzymes. Selenium has a very important function in maintaining immune-endocrine, metabolic and cellular homeostasis. Manganese, on the other hand, is important in development, digestion, reproduction, antioxidant defense, energy production, immune response and regulation of neuronal activity. We review the role of selenium and manganese and their effects on tumor growth, metastasis potential and remodeling of the microenvironment. We also describe their role as potential biomarkers in the diagnosis and the potential for the use of Se- and Mn-containing compounds in composition for the treatment of cancer of the reproductive organs.

Role of Impaired Astrocyte Gap Junction Coupling in Epileptogenesis.

The gap-junction-coupled astroglial network plays a central role in the regulation of neuronal activity and synchronisation, but its involvement in the pathogenesis of neuronal diseases is not yet understood. Here, we present the current state of knowledge about the impact of impaired glial coupling in the development and progression of epilepsy and discuss whether astrocytes represent alternative therapeutic targets. We focus mainly on temporal lobe epilepsy (TLE), which is the most common form of epilepsy in adults and is characterised by high therapy resistance. Functional data from TLE patients and corresponding experimental models point to a complete loss of astrocytic coupling, but preservation of the gap junction forming proteins connexin43 and connexin30 in hippocampal sclerosis. Several studies further indicate that astrocyte uncoupling is a causal event in the initiation of TLE, as it occurs very early in epileptogenesis, clearly preceding dysfunctional changes in neurons. However, more research is needed to fully understand the role of gap junction channels in epilepsy and to develop safe and effective therapeutic strategies targeting astrocytes.

Information Encoding in Bursting Spiking Neural Network Modulated by Astrocytes.

We investigated a mathematical model composed of a spiking neural network (SNN) interacting with astrocytes. We analysed how information content in the form of two-dimensional images can be represented by an SNN in the form of a spatiotemporal spiking pattern. The SNN includes excitatory and inhibitory neurons in some proportion, sustaining the excitation-inhibition balance of autonomous firing. The astrocytes accompanying each excitatory synapse provide a slow modulation of synaptic transmission strength. An information image was uploaded to the network in the form of excitatory stimulation pulses distributed in time reproducing the shape of the image. We found that astrocytic modulation prevented stimulation-induced SNN hyperexcitation and non-periodic bursting activity. Such homeostatic astrocytic regulation of neuronal activity makes it possible to restore the image supplied during stimulation and lost in the raster diagram of neuronal activity due to non-periodic neuronal firing. At a biological point, our model shows that astrocytes can act as an additional adaptive mechanism for regulating neural activity, which is crucial for sensory cortical representations.

Bursting Dynamics of Spiking Neural Network Induced by Active Extracellular Medium

We propose a mathematical model of a spiking neural network (SNN) that interacts with an active extracellular field formed by the brain extracellular matrix (ECM). The SNN exhibits irregular spiking dynamics induced by a constant noise drive. Following neurobiological facts, neuronal firing leads to the production of the ECM that occupies the extracellular space. In turn, active components of the ECM can modulate neuronal signaling and synaptic transmission, for example, through the effect of so-called synaptic scaling. By simulating the model, we discovered that the ECM-mediated regulation of neuronal activity promotes spike grouping into quasi-synchronous population discharges called population bursts. We investigated how model parameters, particularly the strengths of ECM influence on synaptic transmission, may facilitate SNN bursting and increase the degree of neuronal population synchrony.

SOCE as a regulator of neuronal activity.

Store operated Ca2+ entry (SOCE) is a ubiquitous signalling module with established roles in the immune system, secretion and muscle development. Recent evidence supports a complex role for SOCE in the nervous system. In this review we present an update of the current knowledge on SOCE function in the brain with a focus on its role as a regulator of brain activity and excitability.

Amyloid-β Protein Precursor Regulates Electrophysiological Properties in the Hippocampus via Altered Kv1.4 Expression and Function in Mice.

Amyloid-β protein precursor (AβPP) is enriched in neurons. However, the mechanism underlying AβPP regulation of neuronal activity is poorly understood. Potassium channels are critically involved in neuronal excitability. In hippocampus, A-type potassium channels are highly expressed and involved in determining neuronal spiking. We explored hippocampal local field potential (LFP) and spiking in the presence and absence of AβPP, and the potential involvement of an A-type potassium channel. We used in vivo extracellular recording and whole-cell patch-clamp recording to determine neuronal activity, current density of A-type potassium currents, and western blot to detect changes in related protein levels. Abnormal LFP was observed in AβPP-/- mice, including reduced beta and gamma power, and increased epsilon and ripple power. The firing rate of glutamatergic neurons reduced significantly, in line with an increased action potential rheobase. Given that A-type potassium channels regulate neuronal firing, we measured the protein levels and function of two major A-type potassium channels and found that the post-transcriptional level of Kv1.4, but not Kv4.2, was significantly increased in the AβPP-/- mice. This resulted in a marked increase in the peak time of A-type transient outward potassium currents in both glutamatergic and gamma-aminobutyric acid-ergic (GABAergic) neurons. Furthermore, a mechanistic experiment using human embryonic kidney 293 (HEK293) cells revealed that the AβPP deficiency-induced increase in Kv1.4 may not involve protein-protein interaction between AβPP and Kv1.4. This study suggests that AβPP modulates neuronal firing and oscillatory activity in the hippocampus, and Kv1.4 may be involved in mediating the modulation.