Properties Of CA1 Pyramidal Neurons Research Articles

Changes in neuronal excitability in the rat hippocampus in a prolonged febrile seizures model

Febrile seizures (FSs) are a prevalent neurological disorder among children aged 3 months to 5 years, with the highest incidence observed in the second year of life [1]. Considering that neuronal and glial cell development and synaptic contact formation are ongoing during this period [2, 3], FSs can potentially influence these processes. However, the present data on the effect of FSs on brain development remain inconsistent. This study aims to examine the impact of extended seizures on the attributes of hippocampal pyramidal neurons in rats of varying ages. Wistar rats were used in this study. FSs were induced on postnatal day (P)10 through placing pups onto the bottom of a glass chamber for 30 minutes and exposing them to a controlled stream of heated air, causing their body temperature to rise to 39 °C and trigger the occurrence of FSs. Only animals that underwent FSs that persisted for at least 15 minutes were included in the study. Littermates were employed as controls and were placed away from the nest for the same duration but kept at room temperature. At postnatal days 12, 21–23, and 51–55, the rats were decapitated, and their brains were extracted. Horizontal brain slices (400 micrometers) were sliced. The study examined the biophysical properties of CA1 pyramidal neurons using the whole-cell patch-clamp method. 1.5-second current pulses were injected, and subthreshold membrane properties such as resting membrane potential, input resistance, membrane time constant, and intrinsic firing properties, were assessed. Extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 stratum radiatum of the hippocampus to assess the efficacy of synaptic neurotransmission at CA3-CA1 pyramidal neuron synapses. The amplitude and fiber volley (FV) amplitude of each fEPSP were measured by applying high amplitude currents to each slice. A sigmoidal Gompertz function was used to evaluate the efficacy of neurotransmission. Paired-pulse stimulation was used to examine potential alterations in short-term synaptic plasticity. Paired pulses were administered at intervals spanning from 10 to 500 ms, and the paired-pulse ratio (PPR) was assessed as the proportion of the amplitude of the second to the first fEPSP for each interval. Maximum electroshock seizure threshold (MEST) was determined two months after FS to assess the animals’ susceptibility to seizures. The lowest current at which tonic hind limb extension was exhibited was determined for every animal. No significant changes in subthreshold firing properties were observed in P12 or P21 rats following FSs. However, we did observe several changes in intrinsic firing properties. For example, the maximum firing frequency decreased by 23% in P12 rats exposed to FSs, relative to age-matched control rats. Additionally, we noticed that firing frequency adaptation was significantly less pronounced in P12 rats that underwent FSs, compared to control rats of the same age. Seizure-induced alterations in firing characteristics were absent in P21 rats. No significant variations in fEPSP or FV amplitudes were found among the different groups of P12 and P55 rats at different current intensities. However, a significant increase in FV amplitudes and decrease in neuronal input-output (I/O) relationships between fEPSP and FV amplitudes were observed in P21 rats following FSs. At P12, short-term synaptic plasticity was disrupted, evidenced by a significant increase in PPR in rats two days post-FS. However, at P21 and P55, experimental and control groups were not significantly different. MEST test displayed a significant rise in the hind limb extension threshold in rats two months following FS as compared to control animals. Overall, these findings suggest alterations in neuronal excitability after prolonged FS. Two days after FS, neuronal excitability transiently decreased while PPR increased, indicating a decrease in the probability of presynaptic glutamate release in hippocampal neurons. The efficiency of synaptic neurotransmission in CA3-CA1 was reduced in three-week-old animals. Additionally, the MEST test demonstrated that rats, two months following FS, exhibited a higher hind limb extension threshold in comparison to control animals.

Deleterious and protective effects of epothilone-D alone and in the context of amyloid β- and tau-induced alterations.

Amyloid-β (Aβ) and hyperphosphorylated tau (P-tau) are Alzheimer's disease (AD) biomarkers that interact in a complex manner to induce most of the cognitive and brain alterations observed in this disease. Since the neuronal cytoskeleton is a common downstream pathological target of tau and Aβ, which mostly lead to augmented microtubule instability, the administration of microtubule stabilizing agents (MSAs) can protect against their pathological actions. However, the effectiveness of MSAs is still uncertain due to their state-dependent negative effects; thus, evaluating their specific actions in different pathological or physiological conditions is required. We evaluated whether epothilone-D (Epo-D), a clinically used MSA, rescues from the functional and behavioral alterations produced by intracerebroventricular injection of Aβ, the presence of P-tau, or their combination in rTg4510 mice. We also explored the side effects of Epo-D. To do so, we evaluated hippocampal-dependent spatial memory with the Hebb-Williams maze, hippocampal CA1 integrity and the intrinsic and synaptic properties of CA1 pyramidal neurons with the patch-clamp technique. Aβ and P-tau mildly impaired memory retrieval, but produced contrasting effects on intrinsic excitability. When Aβ and P-tau were combined, the alterations in excitability and spatial reversal learning (i.e., cognitive flexibility) were exacerbated. Interestingly, Epo-D prevented most of the impairments induced Aβ and P-tau alone and combined. However, Epo-D also exhibited some side effects depending on the prevailing pathological or physiological condition, which should be considered in future preclinical and translational studies. Although we did not perform extensive histopathological evaluations or measured microtubule stability, our findings show that MSAs can rescue the consequences of AD-like conditions but otherwise be harmful if administered at a prodromal stage of the disease.

Pre- and post-synaptic roles for DCC in memory consolidation in the adult mouse hippocampus

The receptor deleted in colorectal cancer (DCC) and its ligand netrin-1 are essential for axon guidance during development and are expressed by neurons in the mature brain. Netrin-1 recruits GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and is critical for long-term potentiation (LTP) at CA3-CA1 hippocampal Schaffer collateral synapses, while conditional DCC deletion from glutamatergic neurons impairs hippocampal-dependent spatial memory and severely disrupts LTP induction. DCC co-fractionates with the detergent-resistant component of postsynaptic density, yet is enriched in axonal growth cones that differentiate into presynaptic terminals during development. Specific presynaptic and postsynaptic contributions of DCC to the function of mature neural circuits have yet to be identified. Employing hippocampal subregion-specific conditional deletion of DCC, we show that DCC loss from CA1 hippocampal pyramidal neurons resulted in deficits in spatial memory, increased resting membrane potential, abnormal dendritic spine morphology, weaker spontaneous excitatory postsynaptic activity, and reduced levels of postsynaptic adaptor and signaling proteins; however, the capacity to induce LTP remained intact. In contrast, deletion of DCC from CA3 neurons did not induce detectable changes in the intrinsic electrophysiological properties of CA1 pyramidal neurons, but impaired performance on the novel object place recognition task as well as compromised excitatory synaptic transmission and LTP at Schaffer collateral synapses. Together, these findings reveal specific pre- and post-synaptic contributions of DCC to hippocampal synaptic plasticity underlying spatial memory.

Low-frequency Stimulation Decreases Hyperexcitability Through Adenosine A1 Receptors in the Hippocampus of Kindled Rats.

Introduction:In this study, the role of A1 adenosine receptors in improving the effect of Low-Frequency Electrical Stimulation (LFS) on seizure-induced hyperexcitability of hippocampal CA1 pyramidal neurons was investigated.Methods:A semi-rapid hippocampal kindling model was used to induce seizures in male Wistar rats. Examination of the electrophysiological properties of CA1 pyramidal neurons of the hippocampus using whole-cell patch-clamp recording 48 h after the last kindling stimulation revealed that the application of LFS as two packages of stimulations at a time interval of 6 h for two consecutive days could significantly restore the excitability CA1 pyramidal neurons evidenced by a decreased in the of the number of evoked action potentials and enhancement of amplitude, maximum rise slope and decay slope of the first evoked action potential, rheobase, utilization time, adaptation index, first-spike latency, and post-AHP amplitude. Selective locked of A1 receptors by the administration of 8-Cyclopentyl-1,3-dimethylxanthine (1 μM, 1 μl, i.c.v.) before applying each LFS package, significantly reduced LFS effectiveness in recovering these parameters.Results:On the other hand, selective activation of A1 receptors by an injection of N6-cyclohexyladenosine (10 μM, 1 μl, i.c.v.), instead of LFS application, could imitate LFS function in improving these parameters.Conclusion:It is suggested that LFS exerts its efficacy on reducing the neuronal excitability, partially by activating the adenosine system and activating its A1 receptors.

Differential developmental refinement of the intrinsic electrophysiological properties of CA1 pyramidal neurons from the rat dorsal and ventral hippocampus.

The dorsal and ventral regions of the rat longitudinal hippocampal axis are functionally distinct. That is, each region is associated with different behavioral tasks and disease susceptibilities due to underlying anatomical, and physiological differences. These differences are especially pronounced in area CA1, where significant differences in morphology, synaptic physiology, intrinsic excitability, and gene expression have been reported between CA1 pyramidal neurons from the dorsal (DHC) and ventral hippocampus (VHC). However, despite a significant amount of recent attention, a cogent picture of the intrinsic electrophysiological profile of DHC and VHC neurons has remained elusive, due, in part, to experiments performed on rats at different developmental time points. Moreover, the resulting intrinsic electrophysiological profiles are sufficiently different as to warrant a thorough investigation of the spatial and temporal changes in the intrinsic excitability of CA1 pyramidal neurons across developmental time. Accordingly, in this study, I have characterized the intrinsic electrophysiological properties of CA1 pyramidal neurons from acute hippocampal slices prepared from the DHC and VHC throughout an approximately 3-week developmental period (P14-P37). DHC and VHC neurons exhibited distinct intra-region changes (DHC or VHC) and inter-region differences (DHC versus VHC) in their intrinsic electrophysiological properties, which yielded two developmental timelines: (a) a common developmental timeline describing changes observed in both DHC and VHC neurons, and (b) a differential developmental timeline highlighting unique features observed in DHC neurons. Specifically, DHC neurons exhibited significant inter-region differences in RMP, input resistance, threshold, and spike frequency adaptation relative to VHC neurons, as well as an intra-region change in the rebound slope (a proxy for Ih ). These observations both integrate and reconcile previous work performed with rats at different developmental stages and suggest a distinct developmental trajectory for DHC neurons that might shed light on the normal physiological functions and disease susceptibility of the DHC.

Overexpression of Kcnmb2 in Dorsal CA1 of Offspring Mice Rescues Hippocampal Dysfunction Caused by a Methyl Donor-Rich Paternal Diet

BK channels are known regulators of neuronal excitability, synaptic plasticity, and memory. Our previous study showed that a paternal methyl donor-rich diet reduced the expression of Kcnmb2, which encodes BK channel subunit beta 2, and caused memory deficits in offspring mice. To explore the underlying cellular mechanisms, we investigated the intrinsic and synaptic properties of CA1 pyramidal neurons of the F1 offspring mice whose fathers were fed with either a methyl donor-rich diet (MD) or regular control diet (CD) for 6 weeks before mating. Whole-cell patch-clamp recordings of CA1 pyramidal neurons revealed a decrease in intrinsic excitability and reduced frequency of inhibitory post-synaptic currents in MD F1 mice compared to the CD F1 controls. AAV-based overexpression of Kcnmb2 in dorsal CA1 ameliorated changes in neuronal excitability, synaptic transmission, and plasticity in MD F1 mice. Our findings thus indicate that a transient paternal exposure to a methyl donor-rich diet prior to mating alters Kcnmb2-sensitive hippocampal functions in offspring animals.

Long‐term high‐intensity sound stimulation inhibits Ih in CA1 pyramidal neurons.

Afferent neurotransmission on hippocampal pyramidal cells can change their intrinsic membrane properties and affect many ion currents. One of the most plastic neuronal currents is the hyperpolarization activated cationic current (Ih), which changes in CA1 pyramidal cells in responseto many types of physiological and pathological processes. Several evidences demonstrated that hippocampal CA1 pyramidal neurons are affected by auditory stimulation. Recently we demonstrated that long‐term potentiation (LTP) is depressed by high‐intensity sound stimulation. Here we investigated if a long‐term high‐intensity sound stimulation could affect intrinsic membrane properties of CA1 pyramidal neurons. Our results showed that Ih is depressed by longterm (2 minutes per day, for 10 days) high intensity sound (110 dB) exposure. This resulted in a decreased resting membrane potential, increased membrane input resistance and time constant, and decreased action potential threshold. In contrast, CA1 pyramidal neurons from sound‐exposed animals fired more action potentials than neurons from control animals, but this effect was not caused by a decreased Ih. Interestingly, a single episode (1 minute) of 110 dB sound stimulation which also inhibits hippocampal LTP did not affect Ih and firing in pyramidal neurons, suggesting that these are long‐term responses to high intensity sound exposure. Our results show that prolonged exposure to high‐intensity sound affects intrinsic membrane properties of hippocampal pyramidal neurons mainly by decreasing the amplitude of Ih.Support or Funding InformationFAPESP, CNPQ and CapesThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Low-Frequency Electrical Stimulation on the High-K+-Induced Neuronal Hyperexcitability in Rat Hippocampal Slices

Low-frequency electrical stimulation (LFS) is a potential therapeutic method for epilepsy treatment. However, the effect of different LFS characteristics including the number of pulses, intensity and the time of application on its antiepileptic action has not been completely determined. In the present study, epileptiform activity (EA) was induced in hippocampal slices by high-K+ solution which was washed out after 20 min. The changes in the electrophysiological properties of CA1 pyramidal neurons were measured during and 30 min after EA using whole-cell patch-clamp recording. EA occurrence resulted in neuronal hyperexcitability. Application of 1-Hz LFS to the Schaffer collaterals at 600 and 900 pulses and two intensities (equal and 1.5 times more than an intensity sufficient to elicits a 5-mV EPSP) at the beginning of EA showed that 900-pulse LFS at high intensity had stronger preventing effect on high-K+-induced neuronal hyperexcitability by increasing the rheobase current, utilization time, first-spike latency, delay to first-rebound action potential and decreasing the number of rebound action potential. In addition, application of high-intensity 900-pulse LFS had better inhibitory effect on the neuronal hyperexcitability when applied at the beginning of EA compared to its administration before or at 8–10 min after EA. Therefore, it may suggest the inhibitory action of LFS on the neuronal hyperexcitability is augmented by increasing its number of pulses and intensity. In addition, there is a time window for LFS application so that its application at the beginning of EA has better inhibitory effect.

Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy.

Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention.

Mapping the electrophysiological and morphological properties of CA1 pyramidal neurons along the longitudinal hippocampal axis.

Differences in behavioral roles, anatomical connectivity, and gene expression patterns in the dorsal, intermediate, and ventral regions of the hippocampus are well characterized. Relatively fewer studies have, however, focused on comparing the physiological properties of neurons located at different dorsoventral extents of the hippocampus. Recently, we reported that dorsal CA1 neurons are less excitable than ventral neurons. There is little or no information for how neurons in the intermediate hippocampus compare to those from the dorsal and ventral ends. Also, it is not known whether the transition of properties along the dorsoventral axis is gradual or segmented. In this study, we developed a statistical model to predict the dorsoventral position of transverse hippocampal slices. Using current clamp recordings combined with this model, we found that CA1 neurons in dorsal, intermediate, and ventral hippocampus have distinct electrophysiological and morphological properties and that the transition in most (but not all) of these properties from the ventral to dorsal end is gradual. Using linear and segmented regression analyses, we found that input resistance and resting membrane potential changed linearly along the V-D axis. Interestingly, the transition in resonance frequency, rebound slope, dendritic branching in stratum radiatum, and action potential properties was segmented along the V-D axis. Together, the findings from this study highlight the heterogeneity in CA1 neuronal properties along the entire longitudinal axis of hippocampus.

Increased excitability and excitatory synaptic transmission during in vitro ischemia in the neonatal mouse hippocampus

Objective: The present study tested the hypothesis that exposure to in vitro hypoxia–ischemia alters membrane properties and excitability as well as excitatory synaptic transmission of CA1 pyramidal neurons in the neonatal mouse. Methods: Experiments were conducted in hippocampal slices in P7–P9 C57Bl/6 mice using whole-cell patch clamp in current- and voltage-clamp mode. Passive membrane potential (Vm), input resistance (Rin) and active (action potential (AP) threshold and amplitude) membrane properties of CA1 pyramidal neurons were assessed at baseline, during 10min in vitro ischemia (oxygen-glucose deprivation (OGD)) and during reoxygenation. Spontaneous and miniature excitatory post-synaptic currents (s and mEPSCs) were studied under similar conditions. Results: OGD caused significant depolarization of CA1 pyramidal neurons as well as decrease in AP threshold and increase in AP amplitude. These changes were blocked by the application of tetrodotoxin (TTX), indicating Na+ channels’ involvement. Following 10min of reoxygenation, significant membrane hyperpolarization was noted and it was associated with a decrease in Rin. AP threshold and amplitude returned to baseline during that stage. sEPSC and mEPSC frequency increased during both OGD and reoxygenation but their amplitude remained unchanged. Additionally, we found that OGD decreases Ih (hyperpolarization activated current) in CA1 neurons from neonatal mice and this effect persists during reoxygenation. Significance: These results indicate that in vitro ischemia leads to changes in membrane excitability mediated by sodium and potassium channels. Further, it results in enhanced neurotransmitter release from presynaptic terminals. These changes are likely to represent one of the mechanisms of hypoxia/ischemia-mediated seizures in the neonatal period.

Alterations in CA1 pyramidal neuronal intrinsic excitability mediated by Ih channel currents in a rat model of amyloid beta pathology

Amyloid beta (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer’s disease (AD) by changing the neuronal excitability. However, the cellular mechanisms by which accumulation of Aβ affects intrinsic neuronal properties are not well understood. The effect of bilateral intra-frontal cortex Aβ (1–42) peptide injection on the intrinsic excitability of hippocampal CA1 pyramidal neurons with particular focus on the contribution of hyperpolarization-activated (Ih) channel currents was examined using whole-cell patch-clamp recording. Passive avoidance memory impairment and morphological changes in rats receiving intra-frontal Aβ treatment were observed, which was associated with significant changes both in passive and active intrinsic electrical membrane properties of CA1 pyramidal neurons. Electrophysiological recording showed a significant decrease in neuronal excitability associated with an augmentation in the first spike after-hyperpolarization (AHP) amplitude. In addition, the depolarizing sag voltage was altered in neurons recorded from Aβ-treated group. In voltage-clamp condition, a hyperpolarizing activated inward current sensitive to ZD7288 and capsaicin was significantly increased in neurons from Aβ-treated rats. The Ih current density was increased and the activation curve was shifted toward less negative potential in the Aβ-treated group as compared to control group. The enhancing effect of Aβ treatment on Ih current was confirmed by showing upregulation of the mRNA of HCN1 channel in the CA1 pyramidal layer of hippocampi.These findings suggest the contribution of Ih and possibly TRPV1 channel currents to the changes induced by Aβ treatment in the intrinsic membrane properties, which, in turn, may provide therapeutic targets for treatment of AD.

The therapeutic potential of berberine against the altered intrinsic properties of the CA1 neurons induced by Aβ neurotoxicity

It was demonstrated that treatment with beta amyloid (Aβ) led to extreme alterations in the intrinsic electrophysiological properties of CA1 pyramidal neurons. Also, malfunction of the cholinergic system is correlated to the memory and cognitive impairments. Several new studies have suggested that Berberis vulgaris can act as a cholinesterase inhibitor. The present study aimed to investigate the effects of berberine (BER) on the Aβ-induced impairments in learning and memory. The male Wistar rats were divided into 4 groups of Sham, BER, Aβ and Aβ+BER. The administration of BER or its vehicle started immediately after the injection of Aβ and followed by 13 days. Then, the animals were tested for learning and memory performance using the Morris water maze (MWM) and passive avoidance tests. Then, they were sacrificed for the whole cell patch clamp recording. The results of the MWM and passive avoidance tasks indicated that administration of the BER in the Aβ+BER group prevented the memory impairment induced by Aβ. The results of the whole cell patch clamp also showed that administration of the BER restored the Aβ-induced impairments in the firing frequency, half-width and rebound action potential. These results suggested that administration of the BER could ameliorate neurotoxicity induced by Aβ. However, this neuroprotection impact could be resulted from the balance effect of the Ca2+ entry. The optimal level of Ca2+ entry by BER could be a major factor that modified the function of the Ca2+-activated K+ channels and decreased the half-width in the Aβ treated rats.

Computational diversity in the hippocampus: a matter of components.

Computational diversity in the hippocampus: a matter of components.

Intrinsic excitability changes induced by acute treatment of hippocampal CA1 pyramidal neurons with exogenous amyloid β peptide.

ABSTRACTAccumulation of beta‐amyloid (Aβ) peptides in the human brain is a canonical pathological hallmark of Alzheimer's disease (AD). Recent work in Aβ‐overexpressing transgenic mice indicates that increased brain Aβ levels can be associated with aberrant epileptiform activity. In line with this, such mice can also exhibit altered intrinsic excitability (IE) of cortical and hippocampal neurons: these observations may relate to the increased prevalence of seizures in AD patients. In this study, we examined what changes in IE are produced in hippocampal CA1 pyramidal cells after 2–5 h treatment with an oligomeric preparation of synthetic human Aβ 1–42 peptide. Whole cell current clamp recordings were compared between Aβ‐(500 nM) and vehicle‐(DMSO 0.05%) treated hippocampal slices obtained from mice. The soluble Aβ treatment did not produce alterations in sub‐threshold intrinsic properties, including membrane potential, input resistance, and hyperpolarization activated “sag”. Similarly, no changes were noted in the firing profile evoked by 500 ms square current supra‐threshold stimuli. However, Aβ 500 nM treatment resulted in the hyperpolarization of the action potential (AP) threshold. In addition, treatment with Aβ at 500 nM depressed the after‐hyperpolarization that followed both a single AP or 50 Hz trains of a number of APs between 5 and 25. These data suggest that acute exposure to soluble Aβ oligomers affects IE properties of CA1 pyramidal neurons differently from outcomes seen in transgenic models of amyloidopathy. However, in both chronic and acute models, the IE changes are toward hyperexcitability, reinforcing the idea that amyloidopathy and increased incidence in seizures might be causally related in AD patients. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Hippocampal function is compromised in an animal model of multiple sclerosis

Multiple sclerosis (MS) is a progressive inflammatory autoimmune disease that is characterized by demyelination and axonal damage in the nervous system. One obvious consequence is a cumulative loss of muscle control. However, cognitive dysfunction affects roughly half of MS sufferers, sometimes already early in the disease course. Although long-term (remote) memory is typically unaffected, the ability to form new declarative memories becomes compromised. A major structure for the encoding of new declarative memories is the hippocampus. Encoding is believed to be mediated by synaptic plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength. Here, in an animal model of MS we explored whether disease symptoms are accompanied by a loss of functional neuronal integrity, synaptic plasticity, or hippocampus-dependent learning ability. In mice that developed MOG35–55-induced experimental autoimmune encephalomyelitis (EAE), passive properties of CA1 pyramidal neurons were unaffected, although the ability to fire action potentials became reduced in the late phase of EAE. LTP remained normal in the early phase of MOG35–55-induced EAE. However, in the late phase, LTP was impaired and LTP-related spatial memory was impaired. In contrast, LTD and hippocampus-dependent object recognition memory were unaffected. These data suggest that in an animal model of MS hippocampal function becomes compromised as the disease progresses.

Proton radiation alters intrinsic and synaptic properties of CA1 pyramidal neurons of the mouse hippocampus.

High-energy protons constitute at least 85% of the fluence of energetic ions in interplanetary space. Although protons are only sparsely ionizing compared to higher atomic mass ions, they nevertheless significantly contribute to the delivered dose received by astronauts that can potentially affect central nervous system function at high fluence, especially during prolonged deep space missions such as to Mars. Here we report on the long-term effects of 1 Gy proton irradiation on electrophysiological properties of CA1 pyramidal neurons in the mouse hippocampus. The hippocampus is a key structure for the formation of long-term episodic memory, for spatial orientation and for information processing in a number of other cognitive tasks. CA1 pyramidal neurons form the last and critical relay point in the trisynaptic circuit of the hippocampal principal neurons through which information is processed before being transferred to other brain areas. Proper functioning of CA1 pyramidal neurons is crucial for hippocampus-dependent tasks. Using the patch-clamp technique to evaluate chronic effects of 1 Gy proton irradiation on CA1 pyramidal neurons, we found that the intrinsic membrane properties of CA1 pyramidal neurons were chronically altered at 3 months postirradiation, resulting in a hyperpolarization of the resting membrane potential (VRMP) and a decrease in input resistance (Rin). These small but significant alterations in intrinsic properties decreased the excitability of CA1 pyramidal neurons, and had a dramatic impact on network function in a computational model of the CA1 microcircuit. We also found that proton-radiation exposure upregulated the persistent Na(+) current (INaP) and increased the rate of miniature excitatory postsynaptic currents (mEPSCs). Both the INaP and the heightened rate of mEPSCs contribute to neuronal depolarization and excitation, and at least in part, could compensate for the reduced excitability resulting from the radiation effects on the VRMP and the Rin. These results show long-term alterations in the intrinsic properties of CA1 pyramidal cells after realistic, low-dose proton irradiation.

Simvastatin Treatment Enhances NMDAR-Mediated Synaptic Transmission by Upregulating the Surface Distribution of the GluN2B Subunit

The ramifications of statins on plasma cholesterol and coronary heart disease have been well documented. However, there is increasing evidence that inhibition of the mevalonate pathway may provide independent neuroprotective and procognitive pleiotropic effects, most likely via inhibition of isoprenoids, mainly farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). FPP and GGPP are the major donors of prenyl groups for protein prenylation. Modulation of isoprenoid availability impacts a slew of cellular processes including synaptic plasticity in the hippocampus. Our previous work has demonstrated that simvastatin (SV) administration improves hippocampus-dependent spatial memory, rescuing memory deficits in a mouse model of Alzheimer's disease. Treatment of hippocampal slices with SV enhances long-term potentiation (LTP), and this effect is dependent on the activation of Akt (protein kinase B). Further studies showed that SV-induced enhancement of hippocampal LTP is driven by depletion of FPP and inhibition of farnesylation. In the present study, we report the functional consequences of exposure to SV at cellular/synaptic and molecular levels. While application of SV has no effect on intrinsic membrane properties of CA1 pyramidal neurons, including hyperpolarization-activated cyclic-nucleotide channel-mediated sag potentials, the afterhyperpolarization (AHP), and excitability, SV application potentiates the N-methyl D-aspartate receptor (NMDAR)-mediated contribution to synaptic transmission. In mouse hippocampal slices and human neuronal cells, SV treatment increases the surface distribution of the GluN2B subunit of the NMDAR without affecting cellular cholesterol content. We conclude that SV-induced enhancement of synaptic plasticity in the hippocampus is likely mediated by augmentation of synaptic NMDAR components that are largely responsible for driving synaptic plasticity in the CA1 region.

Maternal mobile phone exposure alters intrinsic electrophysiological properties of CA1 pyramidal neurons in rat offspring

Some studies have shown that exposure to electromagnetic field (EMF) may result in structural damage to neurons. In this study, we have elucidated the alteration in the hippocampal function of offspring Wistar rats (n = 8 rats in each group) that were chronically exposed to mobile phones during their gestational period by applying behavioral, histological, and electrophysiological tests. Rats in the EMF group were exposed to 900 MHz pulsed-EMF irradiation for 6 h/day. Whole cell recordings in hippocampal pyramidal cells in the mobile phone groups did show a decrease in neuronal excitability. Mobile phone exposure was mostly associated with a decrease in the number of action potentials fired in spontaneous activity and in response to current injection in both male and female groups. There was an increase in the amplitude of the afterhyperpolarization (AHP) in mobile phone rats compared with the control. The results of the passive avoidance and Morris water maze assessment of learning and memory performance showed that phone exposure significantly altered learning acquisition and memory retention in male and female rats compared with the control rats. Light microscopy study of brain sections of the control and mobile phone-exposed rats showed normal morphology.Our results suggest that exposure to mobile phones adversely affects the cognitive performance of both female and male offspring rats using behavioral and electrophysiological techniques.

Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo

Chronic changes in excitability and activity can induce homeostatic plasticity. These perturbations may be associated with neurological disorders, particularly those involving loss or dysfunction of GABA interneurons. In distal-less homeobox 1 (Dlx1(-/-)) mice with late-onset interneuron loss and reduced inhibition, we observed both excitatory synaptic silencing and decreased intrinsic neuronal excitability. These homeostatic changes do not fully restore normal circuit function, because synaptic silencing results in enhanced potential for long-term potentiation and abnormal gamma oscillations. Transplanting medial ganglionic eminence interneuron progenitors to introduce new GABAergic interneurons, we demonstrate restoration of hippocampal function. Specifically, miniature excitatory postsynaptic currents, input resistance, hippocampal long-term potentiation, and gamma oscillations are all normalized. Thus, in vivo homeostatic plasticity is a highly dynamic and bidirectional process that responds to changes in inhibition.