Atorvastatin enhances kainate‐induced gamma oscillations in rat hippocampal slices

Atorvastatin has been shown to affect cognitive functions in rodents and humans. However, the underlying mechanism is not fully understood. Because hippocampal gamma oscillations (γ, 20–80 Hz) are associated with cognitive functions, we studied the effect of atorvastatin on persistent kainate‐induced γ oscillation in the CA3 area of rat hippocampal slices. The involvement of NMDA receptors and multiple kinases was tested before and after administration of atorvastatin. Whole‐cell current‐clamp and voltage‐clamp recordings were made from CA3 pyramidal neurons and interneurons before and after atorvastatin application. Atorvastatin increased γ power by ~ 50% in a concentration‐dependent manner, without affecting dominant frequency. Whereas atorvastatin did not affect intrinsic properties of both pyramidal neurons and interneurons, it increased the firing frequency of interneurons but not that of pyramidal neurons. Furthermore, whereas atorvastatin did not affect synaptic current amplitude, it increased the frequency of spontaneous inhibitory post‐synaptic currents, but did not affect the frequency of spontaneous excitatory post‐synaptic currents. The atorvastatin‐induced enhancement of γ oscillations was prevented by pretreatment with the PKA inhibitor H89, the ERK inhibitor U0126, or the PI3K inhibitor wortmanin, but not by the NMDA receptor antagonist D‐AP5. Taken together, these results demonstrate that atorvastatin enhanced the kainate‐induced γ oscillation by increasing interneuron excitability, with an involvement of multiple intracellular kinase pathways. Our study suggests that the classical cholesterol‐lowering agent atorvastatin may improve cognitive functions compromised in disease, via the enhancement of hippocampal γ oscillations.     

Presynaptic and postsynaptic modulation of glutamatergic synaptic transmission by activation of α1‐ and β‐adrenoceptors in layer V pyramidal neurons of rat cerebral cortex

Adrenergic agonists have different modulatory effects on excitatory synaptic transmission depending on the receptor subtypes involved. The present study examined the loci of α₁‐ and β‐adrenoceptor agonists, which have opposite effects on excitatory neural transmission, involved in modulation of glutamatergic transmission in layer V pyramidal cells of rat cerebral cortex. Phenylephrine, an α₁‐adrenoceptor agonist, suppressed the amplitude of AMPA receptor‐mediated excitatory postsynaptic currents evoked by repetitive electrical stimulation (eEPSCs, 10 pulses at 33 Hz). The coefficient of variation (CV) of the 1st eEPSC amplitude and paired‐pulse ratio (PPR), which were sensitive to extracellular Ca²⁺ concentration, were not affected by phenylephrine. Phenylephrine suppressed miniature EPSC (mEPSC) amplitude without changing its frequency. In contrast, isoproterenol, a β‐adrenoceptor agonist, strongly increased the amplitude of the 1st eEPSC compared with that of the 2nd to 10th eEPSCs, which resulted in a decrease in PPR. Isoproterenol‐induced enhancement of eEPSC amplitude was accompanied by a decrease in CV. Isoproterenol increased the frequency of mEPSCs without significant effect on amplitude. Phenylephrine suppressed inward currents evoked by puff application of glutamate, AMPA, or NMDA, whereas isoproterenol application was not accompanied by significant changes in these inward currents. These findings suggest that phenylephrine decreases eEPSCs through postsynaptic AMPA or NMDA receptors, while the effects of isoproterenol are mediated by facilitation of glutamate release from presynaptic terminals without effect on postsynaptic glutamate receptors. These two different mechanisms of modulation of excitatory synaptic transmission may improve the “signal‐to‐noise ratio” in cerebral cortex. Synapse 63:269–281, 2009. © 2008 Wiley‐Liss, Inc.     

Amyloid β‐protein suppressed nicotinic acetylcholine receptor‐mediated currents in acutely isolated rat hippocampal CA1 pyramidal neurons

Amyloid β protein (Aβ) is responsible for the deficits of learning and memory in Alzheimer's disease (AD). The high affinity between Aβ and nicotinic acetylcholine receptors (nAChRs) suggests that the impairment of cognitive function in AD might be involved in the Aβ‐induced damage of nAChRs. This study investigated the effects of Aβ fragments on nAChR‐mediated membrane currents in acutely isolated rat hippocampal pyramidal neurons by using whole‐cell patch clamp technique. The results showed that: (1) nonspecific nAChR agonist nicotine, selective α7 nAChR agonist choline, and α4β2 nAChR agonist epibatidine all effectively evoked inward currents in CA1 neurons at normal resting membrane potential, with different desensitization characteristics; (2) acute application of different concentrations (pM–μM) of Aβ25‐35, Aβ31‐35, or Aβ35‐31 alone did not trigger any membrane current, but pretreatment with 1 μM Aβ25‐35 and Aβ31‐35 similarly and reversibly suppressed the nicotine‐induced currents; (3) further, choline‐ and epibatidine‐induced currents were also reversibly suppressed by the Aβ pretreatment, but more prominent for the choline‐induced response. These results demonstrate that the functional activity of both α7 and α4β2 nAChRs in the membrane of acutely isolated hippocampal neurons was significantly downregulated by Aβ treatment, suggesting that nAChRs, especially α7 nAChRs, in the brain may be the important biological targets of neurotoxic Aβ in AD. In addition, the similar suppression of nAChR currents by Aβ25‐35 and Aβ31‐35 suggests that the sequence 31‐35 in Aβ molecule may be a shorter active center responsible for the neurotoxicity of Aβ in AD. Synapse, 2013. © 2012 Wiley Periodicals, Inc.     

Spatio‐temporal dynamics of theta oscillations in hippocampal–entorhinal slices

Theta oscillations (4–12 Hz) are associated with learning and memory and are found in the hippocampus and the entorhinal cortex (EC). The spatio‐temporal organization of rhythmic activity in the hippocampal–EC complex was investigated in vitro. The voltage sensitive absorption dye NK3630 was used to record the changes in aggregated membrane voltage simultaneously from the neuronal networks involved. Oscillatory activity at 7.0 Hz (range, 5.8–8.2) was induced in the slice with the muscarinic agonist carbachol (75–100 μM) in the presence of bicuculline (5 μM). Time relations between all recording sites were analyzed using cross‐correlation functions which revealed systematic phase shifts in the theta oscillation recorded from the different entorhinal and hippocampal subregions. These phase shifts could be interpreted as propagation delays. The oscillation propagates over the slice in a characteristic spatio‐temporal sequence, where the entorhinal cortex leads, followed by the subiculum and then the dentate gyrus (DG), to finally reach the CA3 and the CA1 area. The delay from dentate gyrus to the CA3 area was 12.4 ± 1.1 ms (mean ± s.e.m.) and from the CA3 to the CA1 region it was 10.9 ± 1.9 ms. The propagation delays between the hippocampal subregions resemble the latencies of electrically evoked responses in the same subregions. Removing the entorhinal cortex from the slice changed the spatiotemporal pattern into a more clustered pattern with higher local synchrony. We conclude that in the slice, carbachol‐induced theta oscillations are initiated in the entorhinal cortex. The EC could serve to control the information flow through the neuronal network in the subregions of the hippocampus by synchronizing and/or entraining their responses to external inputs. © 2009 Wiley‐Liss, Inc.     

High‐frequency gamma oscillations coexist with low‐frequency gamma oscillations in the rat visual cortex in vitro

Synchronization of neuronal activity in the visual cortex at low (30–70 Hz) and high gamma band frequencies (> 70 Hz) has been associated with distinct visual processes, but mechanisms underlying high‐frequency gamma oscillations remain unknown. In rat visual cortex slices, kainate and carbachol induce high‐frequency gamma oscillations (fast‐γ; peak frequency ～ 80 Hz at 37°C) that can coexist with low‐frequency gamma oscillations (slow‐γ; peak frequency ～ 50 Hz at 37°C) in the same column. Current‐source density analysis showed that fast‐γ was associated with rhythmic current sink‐source sequences in layer III and slow‐γ with rhythmic current sink‐source sequences in layer V. Fast‐γ and slow‐γ were not phase‐locked. Slow‐γ power fluctuations were unrelated to fast‐γ power fluctuations, but were modulated by the phase of theta (3–8 Hz) oscillations generated in the deep layers. Fast‐γ was spatially less coherent than slow‐γ. Fast‐γ and slow‐γ were dependent on γ‐aminobutyric acid (GABA)_A receptors, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors and gap‐junctions, their frequencies were reduced by thiopental and were weakly dependent on cycle amplitude. Fast‐γ and slow‐γ power were differentially modulated by thiopental and adenosine A₁ receptor blockade, and their frequencies were differentially modulated by N‐methyl‐d ‐aspartate (NMDA) receptors, GluK1 subunit‐containing receptors and persistent sodium currents. Our data indicate that fast‐γ and slow‐γ both depend on and are paced by recurrent inhibition, but have distinct pharmacological modulation profiles. The independent co‐existence of fast‐γ and slow‐γ allows parallel processing of distinct aspects of vision and visual perception. The visual cortex slice provides a novel in vitro model to study cortical high‐frequency gamma oscillations.     

β‐Adrenergic receptors link NO/sGC/PKG signaling to BDNF expression during the consolidation of object recognition long‐term memory

The nitric oxide (NO)/soluble guanylyl cyclase (sGC)/protein kinase G (PKG) pathway is important for memory processing, but the identity of its downstream effectors as well as its actual participation in the consolidation of nonaversive declarative long‐term memory (LTM) remain unknown. Here, we show that training rats in an object recognition (OR) learning task rapidly increased nitrites/nitrates (NOx) content in the CA1 region of the dorsal hippocampus while posttraining intra‐CA1 microinfusion of the neuronal NO synthase (nNOS) inhibitor L‐NN hindered OR LTM retention without affecting memory retrieval or other behavioral variables. The amnesic effect of L‐NN was not state dependent, was mimicked by the sGC inhibitor LY83583 and the PKG inhibitor KT‐5823, and reversed by coinfusion of the NO donor S‐nitroso‐N‐acetylpenicillamine (SNAP) and the PKG activator 8‐bromoguanosine 3′,5′‐cyclic monophosphate (8Br‐cGMP). SNAP did not affect the amnesic effect of LY83583 and KT‐5823. Conversely, 8Br‐cGMP overturned the amnesia induced by LY83583 but not that caused by KT‐5823. Intra‐CA1 infusion of the β‐adrenergic receptor blocker timolol right after training hindered OR LTM and, although coadministration of noradrenaline reversed the amnesia caused by L‐NN, LY83583, and KT5823, the amnesic effect of timolol was unaffected by coinfusion of 8Br‐cGMP or SNAP, indicating that hippocampal β‐adrenergic receptors act downstream NO/sGC/PKG signaling. We also found that posttraining intra‐CA1 infusion of function‐blocking anti‐brain‐derived neurotrophic factor (BDNF) antibodies hampered OR LTM retention, whereas OR training increased CA1 BDNF levels in a nNOS‐ and β‐adrenergic receptor‐dependent manner. Taken together, our results demonstrate that NO/sGC/PKG signaling in the hippocampus is essential for OR memory consolidation and suggest that β‐adrenergic receptors link the activation of this pathway to BDNF expression during the consolidation of declarative memories. © 2009 Wiley‐Liss, Inc.     

Functional α7‐containing nicotinic receptors of NG2‐expressing cells in the hippocampus

In the postnatal central nervous system, glial cells expressing the chondroitin sulfate proteoglycan NG2 (NG2‐cells) constitute a cell population exhibiting several properties of oligodendrocyte precursors such as the ability to proliferate. One particular feature of NG2‐cells is that they express several glutamatergic and GABAergic ionotropic receptors activated by synaptic neurotransmitter release. Here, we used patch‐clamp recordings, immunostaining, calcium imaging, and intracellular labeling to test for the presence of ionotropic nicotinic acetylcholine receptors (nAChRs) in NG2‐cells identified in acute hippocampal slices of mice. We demonstrated that these cells express functional nAChRs during the second postnatal week, i.e., the period in which they become the most abundant proliferative cell type of CA1 stratum radiatum. Pharmacological experiments showed that NG2‐cells express α7‐containing nAChRs. In particular, the powerful positive allosteric modulator of these receptors PNU‐120596 induced a 20‐fold increase of agonist‐induced currents and revealed rises in intracellular calcium concentration upon agonist applications. In addition, nanomolar concentrations of nicotine, which did not induce any response in these cells, largely desensitized nAChR‐mediated currents. These data indicate that the functional expression of Ca²⁺‐permeable α7‐containing nAChRs in hippocampal slices is not restricted to neurons and that the receptors of NG2‐cells can be desensitized by low concentrations of nicotine. © 2009 Wiley‐Liss, Inc.     

Neuropeptide Y‐stimulated [35S]GTPγs functional binding is reduced in the hippocampus after kainate‐induced seizures in mice

Kainate‐induced seizures constitute a model of temporal lobe epilepsy where prominent changes are observed in the hippocampal neuropeptide Y (NPY) system. However, little is known about the functional state and signal transduction of the NPY receptor population resulting from kainate exposure. Thus, in this study, we explored functional NPY receptor activity in the mouse hippocampus and neocortex after kainate‐induced seizures using NPY‐stimulated [³⁵S]GTPγS binding. Moreover, we also studied levels of [¹²⁵I]‐peptide YY (PYY) binding and NPY, Y1, Y2, and Y5 receptor mRNA in these kainate‐treated mice. Functional NPY binding was unchanged up to 12 h post‐kainate, but decreased significantly in all hippocampal regions after 24 h and 1 week. Similarly, a decrease in [¹²⁵I]‐PYY binding was found in the dentate gyrus (DG) 1 week post‐kainate. However, at 2 h, 6 h, and 12 h, [¹²⁵I]‐PYY binding was increased in all regions, and in the CA1 also at 24 h post‐kainate. NPY mRNA levels were prominently increased in hippocampal regions, reaching maximum at 12 and 24 h. Y1 and Y5 mRNA levels were lowered in the DG at 24 and 2 h, respectively, while Y2 mRNA levels were elevated at 24 h in the DG and CA3. This study confirms rat kainate studies by showing pronounced adaptive changes in the mouse hippocampus both with regard to NPY synthesis and NPY receptor synthesis and binding, which may contribute to regulating neuronal seizure susceptibility after kainate. However, the potential seizure‐suppressant effects of increased NPY gene expression at late time points post‐kainate could be attenuated by the novel finding of reduced NPY‐receptor G‐protein activation. Synapse 68:427–436, 2014 . © 2014 Wiley Periodicals, Inc.     

Comparison between spontaneous and kainate-induced gamma oscillations in the mouse hippocampus in vitro

Neuronal synchronization at gamma frequency, implicated in cognition, can be evoked in hippocampal slices by pharmacological activation. We characterized spontaneous small‐amplitude gamma oscillations (SγO) recorded in area CA3 of mouse hippocampal slices and compared it with kainate‐induced gamma oscillations (KγO). SγO had a lower peak frequency, a more sinusoidal waveform and was spatially less coherent than KγO, irrespective of oscillation amplitude. CA3a had the smallest oscillation power, phase‐led CA3c by ～4 ms and had the highest SγO frequency in isolated subslices. During SγO CA3c neurons fired at the rebound of inhibitory postsynaptic potentials (IPSPs) that were associated with a current source in stratum lucidum, whereas CA3a neurons often fired from spikelets, 3–4 ms earlier in the cycle, and had smaller IPSPs. Kainate induced faster/larger IPSPs that were associated with an earlier current source in stratum pyramidale. SγO and KγO power were dependent on α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors, gap junctions and γ‐aminobutyric acid (GABA)_A receptors. SγO was suppressed by elevating extracellular KCl, blocking N‐methyl‐d ‐aspartate (NMDA) receptors or muscarinic receptors, or activating GluR5‐containing kainate receptors. SγO was not affected by blocking metabotropic glutamate receptors or hyperpolarization‐activated currents. The adenosine A₁ receptor antagonist 8‐cyclopentyl‐1,3‐dimethoxyxanthine (8‐CPT) and the CB1 cannabinoid receptor antagonist N‐(piperidin‐1‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide (AM251) increased SγO power, indicating that endogenous adenosine and/or endocannabinoids suppress or prevent SγO in vitro. SγO emerges from a similar basic network as KγO, but differs in involvement of somatically projecting interneurons and pharmacological modulation profile. These observations advocate the use of SγO as a natural model for hippocampal gamma oscillations, particularly during less activated behavioural states.     

Activation of adenylate cyclase‐cyclic AMP‐protein kinase A signaling by corticotropin‐releasing factor within the dorsolateral bed nucleus of the stria terminalis is involved in pain‐induced aversion

Pain is a complex experience involving sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been extensively studied, those underlying its affective component have yet to be elucidated. Recently, we reported that corticotrophin‐releasing factor (CRF)‐induced depolarization in type II neurons within the dorsolateral bed nucleus of the stria terminalis (dlBNST) is critical for pain‐induced aversive responses in rats. However, the intracellular signaling underlying the excitatory effects of CRF and the contribution of such signaling to the induction of pain‐induced aversion remain unclear. In the present study, we addressed these issues by conducting whole‐cell patch‐clamp recordings in rat brain slices and by undertaking behavioral pharmacological analyses. Intracellular perfusion of protein kinase A (PKA) inhibitor Rp‐cyclic adenosine monophosphorothioate (Rp‐cAMPS) or KT5720 suppressed the excitatory effects of CRF in type II dlBNST neurons, and bath application of Rp‐cAMPS also suppressed it. In addition, bath application of forskolin, an adenylate cyclase (AC) activator, mimicked the effects of CRF, and pretreatment with forskolin diminished the excitatory effects of CRF. Furthermore, a conditioned place aversion (CPA) test showed that co‐administration of Rp‐cAMPS with CRF into the dlBNST suppressed CRF‐induced CPA. Intra‐dlBNST injection of Rp‐cAMPS also suppressed pain‐induced CPA. These results suggest that CRF increases excitability of type II dlBNST neurons through activation of the AC‐cAMP‐PKA pathway, thereby causing pain‐induced aversive responses. The present findings shed light on the neuronal mechanisms underlying the negative affective component of pain and may provide therapeutic targets for treating intractable pain accompanied by psychological factors.     

Wake‐promoting actions of noradrenergic α1‐ and β‐receptors within the lateral hypothalamic area

Central norepinephrine exerts potent wake‐promoting effects, in part through the actions of noradrenergic α₁‐ and β‐receptors located in the medial septal and medial preoptic areas. The lateral hypothalamic area (LHA), including the lateral hypothalamus, perifornical area and adjacent dorsomedial hypothalamus, is implicated in the regulation of arousal and receives a substantial noradrenergic innervation. To date the functional significance of this innervation is unknown. The current studies examined the degree to which noradrenergic α₁‐ and β‐receptor stimulation within the rat LHA modulates arousal. Specifically, these studies examined the wake‐promoting effects of intra‐tissue infusions (250 nL) of the α₁‐receptor agonist phenylephrine (10, 20 and 40 nmol) and the β‐receptor agonist isoproterenol (3, 10 and 30 nmol) in rats. Results show that stimulation of LHA α₁‐receptors elicits robust and dose‐dependent increases in waking. In contrast, β‐receptor stimulation within the LHA had relatively modest arousal‐promoting actions. Nonetheless, combined α₁‐ and β‐receptor stimulation elicited additive wake‐promoting effects. Arousal‐promoting hypocretin/orexin (HCRT)‐synthesising neurons are located within the LHA. Therefore, additional immunohistochemical studies examined whether α₁‐receptor‐dependent waking is associated with an activation of HCRT neurons as measured by Fos , the protein product of the immediate–early gene c‐fos. Analyses indicate that although intra‐LHA α₁‐receptor agonist infusion elicited a robust increase in Fos immunoreactivity (ir) in this region, this treatment did not activate HCRT neurons as measured by Fos‐ir. Collectively, these observations indicate that noradrenergic α₁‐receptors within the LHA promote arousal via actions that are independent of HCRT neuronal activation.     

GSK‐3β inhibitors reverse cocaine‐induced synaptic transmission dysfunction in the nucleus accumbens

Nucleus accumbens receives glutamatergic projection from the prefrontal cortex (PFC) and dopaminergic input from the Ventral tegmental area (VTA). Recent studies have suggested a critical role for serine/threonine kinase glycogen synthase kinase 3β (GSK3β) in cocaine‐induced hyperactivity; however, the effect of GSK3β on the modulation of glutamatergic and dopaminergic afferents is unclear. In this study, we found that the GSK3 inhibitors, LiCl (100 mg/kg, i.p.) or SB216763 (2.5 mg/kg, i.p.), blocked the cocaine‐induced hyperlocomotor activity in rats. By employing single‐unit recordings in vivo, we found that pretreatment with either SB216763 or LiCl for 15 min reversed the cocaine‐inhibited firing frequency of medium spiny neuron (MSN) in the nucleus accumbens (NAc). Preperfusion of SB216763 (5 μM) ameliorated the inhibitory effect of cocaine on both the α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) (up to 99 ± 6.8% inhibition) and N‐methyl‐D‐aspartic acid receptor (NMDAR)‐mediate EPSC (up to 73 ± 9.7% inhibition) in the NAc in brain slices. The effect of cocaine on AMPA and NMDA receptor‐mediate excitatory postsynaptic current (EPSC) were mimicked by the D₁‐like receptor agonist SKF 38393 and blocked by the D₁‐like receptor antagonist SCH 23390, whereas D₂‐like receptor agonist or antagonist failed to mimic or to block the action of cocaine. Preperfusion of SB216763 for 5 min also ameliorated the inhibitory effect of SKF38393 on both AMPA and NMDA receptor‐mediated components of EPSC, indicate the effect of SB216763 on cocaine was via the D₁‐like receptor. Moreover, cocaine inhibited the presynaptic release of glutamate in the NAc, and SB216763 reversed this effect. In conclusion, D₁ receptor–GSK3β pathway, which mediates glutamatergic transmission in the NAc core through a presynaptic mechanism, plays an important role in acute cocaine‐induced hyperlocomotion.     

3‐Hz subthreshold oscillations of CA2 neurons In vivo

The CA2 region is unique in the hippocampus; it receives direct synaptic innervations from several hypothalamic nuclei and expresses various receptors of neuromodulators, including adenosine, vasopressin, and oxytocin. Furthermore, the CA2 region may have distinct brain functions, such as the control of instinctive and social behaviors; however, little is known about the dynamics of the subthreshold membrane potentials of CA2 neurons in vivo. We conducted whole‐cell current‐clamp recordings from CA2 pyramidal cells in urethane‐anesthetized mice and monitored the intrinsic fluctuations in their membrane potentials. The CA2 pyramidal cells emitted spontaneous action potentials at mean firing rates of ～0.8 Hz. In approximately half of the neurons, the subthreshold membrane potential oscillated at ～3 Hz. In two neurons, we obtained simultaneous recordings of local field potentials from the CA1 stratum radiatum and demonstrated that the 3‐Hz oscillations of CA2 neurons were not correlated with CA1 field potentials. In tetrodotoxin‐perfused acute hippocampal slices, the membrane potentials of CA2 pyramidal cells were not preferentially entrained to 3‐Hz sinusoidal current inputs, which suggest that intracellular 3‐Hz oscillations reflect the neuronal dynamics of the surrounding networks. © 2016 Wiley Periodicals, Inc.     

Glucocorticoid and β‐adrenergic regulation of hippocampal dendritic spines

Glucocorticoid hormones are particularly potent with respect to enhancing memory formation. Notably, this occurs in close synergy with arousal (i.e., when norepinephrine levels are enhanced). In the present study, we examined whether glucocorticoid and norepinephrine hormones regulate the number of spines in hippocampal primary neurons. We report that brief administration of corticosterone or the β‐adrenergic receptor agonist isoproterenol alone increases spine number. This effect becomes particularly prominent when corticosterone and isoproterenol are administered together. In parallel, corticosterone and isoproterenol alone increased the amplitude of miniature excitatory postsynaptic currents, an effect that is not amplified when both hormones are administered together. The effects of co‐application of corticosterone and isoproterenol on spines could be prevented by blocking the glucocorticoid receptor antagonist RU486. Taken together, both corticosterone and β‐adrenergic receptor activation increase spine number, and they exert additive effects on spine number for which activation of glucocorticoid receptors is permissive.     

In vivo ketogenic diet treatment attenuates pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices from epileptic Kv1.1α knockout mice

The ketogenic diet (KD) is an effective therapy for pediatric refractory epilepsies; however, whether the KD changes the pathologic network oscillations generated by an epileptic brain remains unknown. We have reported that hippocampal CA3 regions of epileptic Kv1.1α knockout (KO) mice generate pathologic sharp waves (SPWs) and high‐frequency oscillations (HFOs) that have higher incidence, longer duration, and fast ripples compared to wild‐type (WT). Synaptic activity of hyperexcitable KO mossy fibers significantly decreased CA3 principal cell spike‐timing reliability, which contributed to this network pathology. In addition, we have demonstrated that the KD reduces seizures by 75% in KO mice. Here, we determined whether 10‐ to 14‐day in vivo KD treatment exerts disease‐modifying effects that alter the spontaneous SPW‐HFO complexes generated by the hippocampal CA3 region of KO mice in vitro using extracellular multielectrode array recordings. We found that KD treatment significantly attenuated the pathologic features of KO SPWs and ripples and reduced the incidence of fast ripples. The KD also improved spike‐timing reliability of KO CA3 principal cells, decreased mossy fiber excitability, increased mossy fiber‐CA3 paired‐pulse ratios, and reduced coupling of field excitatory postsynaptic potentials and population spikes in the CA3 region. Collectively, these data indicate that KD treatment modulates CA3‐generated pathologic oscillations by dampening hyperactive mossy fiber synapses. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Dopamine depresses cholinergic oscillatory network activity in rat hippocampus

The dopaminergic neuronal system is implicated in cognitive processes in a variety of brain regions including the mesolimbic system. We have investigated whether dopamine also affects synchronized network activity in the hippocampus, which has been ascribed to play a pivotal role in memory formation. Gamma frequency (20-80 Hz) oscillations were induced by the cholinergic agonist carbachol. Oscillatory activity was examined in area CA3 of Wistar rat hippocampal slices, employing field potential and intracellular recordings. Application of carbachol initiated synchronized population activity in the gamma band at 40 Hz. Induced gamma activity persisted over hours and required GABAA receptors. Dopamine reversibly decreased the integrated gamma band power of the carbachol rhythm by 62%, while its frequency was not changed. By contrast, individual pyramidal cells recorded during carbachol-induced field gamma activity exhibited theta frequency (5-15 Hz) membrane potential oscillations that were not altered by dopamine. The dopamine effect on the field gamma activity was mimicked by the D1 receptor agonist SKF-383393 and partially antagonized by the D1 antagonist SCH-23390. Conversely, the D2 receptor agonist quinpirole failed to depress the oscillations, and the D2 antagonist sulpiride did not prevent the suppressive dopamine effect. The data indicate that dopamine strongly depresses cholinergic gamma oscillations in area CA3 of rat hippocampus by activation of D1-like dopamine receptors and that this effect is most likely mediated via impairment of interneurons involved in generation and maintenance of the carbachol-induced network rhythm.     

Frequency‐ and state‐dependent effects of hippocampal neural disinhibition on hippocampal local field potential oscillations in anesthetized rats

Reduced inhibitory GABA function, so‐called neural disinhibition, has been implicated in cognitive disorders, including schizophrenia and age‐related cognitive decline. We previously showed in rats that hippocampal disinhibition by local microinfusion of the GABA‐A receptor antagonist picrotoxin disrupted memory and attention and enhanced hippocampal multi‐unit burst firing recorded around the infusion site under isoflurane anesthesia. Here, we analyzed the hippocampal local field potential (LFP) recorded alongside the multi‐unit data. We predicted frequency‐specific LFP changes, based on previous studies implicating GABA in hippocampal oscillations, with the weight of evidence suggesting that disinhibition would facilitate theta and disrupt gamma oscillations. Using a new semi‐automated method based on the kurtosis of the LFP peak‐amplitude distribution as well as on amplitude envelope thresholding, we separated three distinct hippocampal LFP states under isoflurane anesthesia: “burst” and “suppression” states—high‐amplitude LFP spike bursts and the interspersed low‐amplitudeperiods—and a medium‐amplitude “continuous” state. The burst state showed greater overall power than suppression and continuous states and higher relative delta/theta power, but lower relative beta/gamma power. The burst state also showed reduced functional connectivity across the hippocampal recording area, especially around theta and beta frequencies. Overall neuronal firing was higher in the burst than the other two states, whereas the proportion of burst firing was higher in burst and continuous states than the suppression state. Disinhibition caused state‐ and frequency‐dependent LFP changes, tending to increase power at lower frequencies (<20 Hz), but to decrease power and connectivity at higher frequencies (>20 Hz) in burst and suppression states. The disinhibition‐induced enhancement of multi‐unit bursting was also state‐dependent, tending to be more pronounced in burst and suppression states than the continuous state. Overall, we characterized three distinct hippocampal LFP states in isoflurane‐anesthetized rats. Disinhibition changed hippocampal LFP oscillations in a state‐ and frequency‐dependent way. Moreover, the disinhibition‐induced enhancement of multi‐unit bursting was also LFP state‐dependent.     

Melatonin protects against amyloid‐β‐induced impairments of hippocampal LTP and spatial learning in rats

Alzheimer's disease (AD), the most prevalent neurodegenerative disease in the elderly, leads to progressive loss of memory and cognitive deficits. Amyloid‐β protein (Aβ) in the brain is thought to be the main cause of memory loss in AD. Melatonin, an indole hormone secreted by the pineal gland, has been reported to produce neuroprotective effects. We examined whether melatonin could protect Aβ‐induced impairments of hippocampal synaptic plasticity, neuronal cooperative activity, and learning and memory. Rats received bilateral intrahippocampal injection of Aβ1‐42 or Aβ31‐35 followed by intraperitoneal application of melatonin for 10 days, and the effects of chronic melatonin treatment on in vivo hippocampal long‐term potentiation (LTP) and theta rhythm and Morris water maze performance were examined. We showed that intrahippocampal injection of Aβ1‐42 or Aβ31‐35 impaired hippocampal LTP in vivo, while chronic melatonin treatment reversed Aβ1‐42‐ or Aβ31‐35‐induced impairments in LTP induction. Intrahippocampal injection of Aβ31‐35 impaired spatial learning and decreased the power of theta rhythm in the CA1 region induced by tail pinch, and these synaptic, circuit, and learning deficits were rescued by chronic melatonin treatment. These results provide evidence for the neuroprotective action of melatonin against Aβ insults and suggest a strategy for alleviating cognition deficits of AD. Synapse 67:626–636, 2013 . © 2013 Wiley Periodicals, Inc.     

The effects of intra‐hippocampal L‐thyroxine infusion on long‐term potentiation and long‐term depression: A possible role for the αvβ3 integrin receptor

Although the effects of long‐term experimental dysthyroidism on long‐term potentiation (LTP) and long‐term depression (LTD) have been documented, the relationship between LTP/LTD and acute administration of L‐thyroxine (T4) has not been described. Here, we investigated the effects of intra‐hippocampal administration of T4 on synaptic plasticity in the dentate gyrus of the hippocampal formation. After a 15‐minute baseline recording, LTP and LTD were induced by application of high‐ and low‐frequency stimulation protocols, respectively. Infusions of saline or T4 and tetraiodothyroacetic acid (tetrac), a T4 analog that inhibits binding of iodothyronines to the integrin αvβ3 receptor, either alone or together, were made during the stimulation protocols. The averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes, between 55 to 60 minutes, were used as a measure of the LTP/LTD magnitude and were analyzed by two‐way univariate ANOVA with T4 and tetrac as between‐subjects factors. The input–output curves of the infusion groups were comparable to each other, as shown by the non significant interaction observed between stimulus intensity and infused drug. The magnitude of the LTP in T4‐infused rats was significantly lower as compared to saline‐infused rats. Both the PS amplitude and the EPSP slope were depressed more markedly with T4 infusion than with saline, tetrac, and T4 + tetrac infusion. Data of this study provide in vivo evidence that T4 can promote LTD over LTP via the integrin αvβ3 receptor, and that the effect of endogenous T4 on this receptor can be suppressed by tetrac in the hippocampus. © 2016 Wiley Periodicals, Inc.     

Cortical gamma‐oscillations modulated by auditory–motor tasks‐intracranial recording in patients with epilepsy

Human activities often involve hand‐motor responses following external auditory–verbal commands. It has been believed that hand movements are predominantly driven by the contralateral primary sensorimotor cortex, whereas auditory–verbal information is processed in both superior temporal gyri. It remains unknown whether cortical activation in the superior temporal gyrus during an auditory–motor task is affected by laterality of hand‐motor responses. Here, event‐related γ‐oscillations were intracranially recorded as quantitative measures of cortical activation; we determined how cortical structures were activated by auditory‐cued movement using each hand in 15 patients with focal epilepsy. Auditory–verbal stimuli elicited augmentation of γ‐oscillations in a posterior portion of the superior temporal gyrus, whereas hand‐motor responses elicited γ‐augmentation in the pre‐ and postcentral gyri. The magnitudes of such γ‐augmentation in the superior temporal, precentral, and postcentral gyri were significantly larger when the hand contralateral to the recorded hemisphere was required to be used for motor responses, compared with when the ipsilateral hand was. The superior temporal gyrus in each hemisphere might play a greater pivotal role when the contralateral hand needs to be used for motor responses, compared with when the ipsilateral hand does. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.