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.     

Intracellular Ca2+ release‐dependent inactivation of Ca2+ currents in thalamocortical relay neurons

Neuronal Ca²⁺ channels are rapidly inactivated by a mechanism that is termed Ca²⁺‐dependent inactivation (CDI). In this study we investigated the influence of intracellular Ca²⁺ release on CDI of high‐voltage‐activated Ca²⁺ channels in rat thalamocortical relay neurons by combining voltage‐clamp, Ca²⁺ imaging and immunological techniques. Double‐pulse protocols revealed CDI, which depended on the length of the conditioning pulses. Caffeine caused a concentration‐dependent increase in CDI that was accompanied by an increase in the duration of Ca²⁺ transients. Inhibition of ryanodine receptors and endoplasmic Ca²⁺ pumps (by thapsigargin or cyclopiazonic acid) resulted in a reduction of CDI. In contrast, inhibition of inositol 1,4,5‐tris‐phosphate receptors by intracellular application of 2‐aminoethoxy diphenyl borate or heparin did not influence CDI. The block of transient receptor potential channels by extracellular application of 2‐aminoethoxy diphenyl borate, however, resulted in a significant reduction of CDI. The central role of L‐type Ca²⁺ channels was emphasized by the near‐complete block of CDI by nifedipine, an effect only surpassed when Ca²⁺ was replaced by Ba²⁺ and chelated by 1,2‐bis(o‐aminophenoxy)ethane‐N,N,N′,N′,‐tetraacetic acid (BAPTA). Trains of action potential‐like stimuli induced a strong reduction in high‐voltage‐activated Ca²⁺ current amplitude, which was significantly reduced when intracellular Ca²⁺ stores were made inoperative by thapsigargin or Ba²⁺/BAPTA. Western blotting revealed expression of L‐type Ca²⁺ channels in thalamic and hippocampal tissue but not liver tissue. In summary, these results suggest a cross‐signalling between L‐type Ca²⁺ channels and ryanodine receptors that controls the amount of Ca²⁺ influx during neuronal activity.     

Nicotine facilitates long‐term potentiation induction in oriens‐lacunosum moleculare cells via Ca2+ entry through non‐α7 nicotinic acetylcholine receptors

Hippocampal inhibitory interneurons have a central role in the control of network activity, and excitatory synapses that they receive express Hebbian and anti‐Hebbian long‐term potentiation (LTP). Because many interneurons in the hippocampus express nicotinic acetylcholine receptors (nAChRs), we explored whether exposure to nicotine promotes LTP induction in these interneurons. We focussed on a subset of interneurons in the stratum oriens/alveus that were continuously activated in the presence of nicotine due to the expression of non‐desensitizing non‐α7 nAChRs. We found that, in addition to α2 subunit mRNAs, these interneurons were consistently positive for somatostatin and neuropeptide Y mRNAs, and showed morphological characteristics of oriens‐lacunosum moleculare cells. Activation of non‐α7 nAChRs increased intracellular Ca²⁺ levels at least in part via Ca²⁺ entry through their channels. Presynaptic tetanic stimulation induced N‐methyl‐d ‐aspartate receptor‐independent LTP in voltage‐clamped interneurons at −70 mV when in the presence, but not absence, of nicotine. Intracellular application of a Ca²⁺ chelator blocked LTP induction, suggesting the requirement of Ca²⁺ signal for LTP induction. The induction of LTP was still observed in the presence of ryanodine, which inhibits Ca²⁺ ‐induced Ca²⁺ release from ryanodine‐sensitive intracellular stores, and the L‐type Ca²⁺ channel blocker nifedipine. These results suggest that Ca²⁺ entry through non‐α7 nAChR channels is critical for LTP induction. Thus, nicotine affects hippocampal network activity by promoting LTP induction in oriens‐lacunosum moleculare cells via continuous activation of non‐α7 nAChRs.     

Chronic psychosocial stress accelerates impairment of long‐term memory and late‐phase long‐term potentiation in an at‐risk model of Alzheimer's disease

Although it is generally agreed that Aβ contributes to the pathogenesis of AD, its precise role in AD and the reason for the varying intensity and time of onset of the disease have not been elucidated. In addition to genetic factors, environmental issues such as stress may also play a critical role in the etiology of AD. This study examined the effect of chronic psychosocial stress in an at‐risk (treatment with a subpathogenic dose of Aβ; “subAβ”) rat model of AD on long‐term memory by three techniques: memory tests in the radial arm water maze, electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of learning‐ and long‐term memory‐related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAβ rat model of AD was induced by continuous infusion of 160 pmol/day Aβ_1–42 via a 14‐day i.c.v. osmotic pump. All tests showed that subAβ rats were not different from control rats. Result from behavioral tests and electrophysiological recordings showed that infusion of subAβ in chronically stressed rats (stress/subAβ group) caused significant impairment of cognitive functions and late‐phase long‐term potentiation (L‐LTP). Molecular analysis of various signaling molecules after expression of L‐LTP, revealed an increase in the levels of p‐CREB in control, stress, and subAβ rats, but not in the stress/subAβ rats. These findings suggest that the chronic stress‐induced molecular alteration may accelerate the impairment of cognition and synaptic plasticity in individuals “at‐risk” for AD. © 2010 Wiley‐Liss, Inc.     

Corticotropin‐releasing factor infusion into nucleus incertus suppresses medial prefrontal cortical activity and hippocampo‐medial prefrontal cortical long‐term potentiation

The medial prefrontal cortex (mPFC) in the rat has been implicated in a variety of cognitive processes, including working memory and expression of fear memory. We investigated the inputs from a brain stem nucleus, the nucleus incertus (NI), to the prelimbic area of the mPFC. This nucleus strongly expresses corticotropin‐releasing factor type 1 (CRF₁) receptors and responds to stress. A retrograde tracer was used to verify connections from the NI to the mPFC. Retrogradely labelled cells in the NI expressed CRF receptors. Electrophysiological manipulation of the NI revealed that stimulation of the NI inhibited spontaneous neuronal firing in the mPFC. Similarly, CRF infusion into the NI, in order to mimic a stressful condition, inhibited neuronal firing and burst firing in the mPFC. The effect of concurrent high‐frequency stimulation of the NI on plasticity in the hippocampo‐prelimbic medial prefrontal cortical (HP‐mPFC) pathway was studied. It was found that electrical stimulation of the NI impaired long‐term potentiation in the HP‐mPFC pathway. Furthermore, CRF infusion into the NI produced similar results. These findings might account for some of the extra‐pituitary functions of CRF and indicate that the NI may play a role in stress‐driven modulation of working memory and possibly other cognitive processes subserved by the mPFC.     

Possible involvement of transient receptor potential ankyrin 1 in Ca2+ signaling via T‐type Ca2+ channel in mouse sensory neurons

T‐type Ca²⁺ channels and TRPA1 are expressed in sensory neurons and both are associated with pain transmission, but their functional interaction is unclear. Here we demonstrate that pharmacological evidence of the functional relation between T‐type Ca²⁺ channels and TRPA1 in mouse sensory neurons. Low concentration of KCl at 15 mM (15K) evoked increases of intracellular Ca²⁺ concentration ([Ca²⁺]_i), which were suppressed by selective T‐type Ca²⁺ channel blockers. RT‐PCR showed that mouse sensory neurons expressed all subtypes of T‐type Ca²⁺ channel. The magnitude of 15K‐induced [Ca²⁺]_i increase was significantly larger in neurons sensitive to allylisothiocyanate (AITC, a TRPA1 agonist) than in those insensitive to it, and in TRPA1^?/? mouse sensory neurons. TRPA1 blockers diminished the [Ca²⁺]_i responses to 15K in neurons sensitive to AITC, but failed to inhibit 40 mM KCl‐induced [Ca²⁺]_i increases even in AITC‐sensitive neurons. TRPV1 blockers did not inhibit the 15K‐induced [Ca²⁺]_i increase regardless of the sensitivity to capsaicin. [Ca²⁺]_i responses to TRPA1 agonist were enhanced by co‐application with 15K. These pharmacological data suggest the possibility of functional interaction between T‐type Ca²⁺ channels and TRPA1 in sensory neurons. Since TRPA1 channel is activated by intracellular Ca²⁺, we hypothesize that Ca²⁺ entered via T‐type Ca²⁺ channel activation may further stimulate TRPA1, resulting in an enhancement of nociceptive signaling. Thus, T‐type Ca²⁺ channel may be a potential target for TRPA1‐related pain.     

Forebrain NR2B overexpression enhancing fear acquisition and long‐term potentiation in the lateral amygdala

N‐methyl‐d ‐aspartic acid (NMDA) receptor‐dependent long‐term potentiation (LTP) at the thalamus–lateral amygdala (T‐LA) synapses is the basis for acquisition of auditory fear memory. However, the role of the NMDA receptor NR2B subunit in synaptic plasticity at T‐LA synapses remains speculative. In the present study, using transgenic mice with forebrain‐specific overexpression of the NR2B subunit, we have observed that forebrain NR2B overexpression results in enhanced LTP but does not alter long‐term depression (LTD) at the T‐LA synapses in transgenic mice. To elucidate the cellular mechanisms underlying enhanced LTP at T‐LA synapses in these transgenic mice, AMPA and NMDA receptor‐mediated postsynaptic currents have been measured. The data show a marked increasing in the amplitude and decay time of NMDA receptor‐mediated currents in these transgenic mice. Consistent with enhanced LTP at T‐LA synapses, NR2B‐transgenic mice exhibit better performance in the acquisition of auditory fear memory than wild‐type littermates. Our results demonstrate that up‐regulation of NR2B expression facilitates acquisition of auditory cued fear memory and enhances LTP at T‐LA synapses.     

Plasticity of synaptic glun receptors is required for the Src‐dependent induction of long‐term potentiation at CA3‐CA1 synapses

The induction of long‐term potentiation (LTP) of CA3‐CA1 synapses requires activation of postsynaptic N‐methyl‐D ‐aspartate receptors (GluNRs). At resting potential, the contribution of GluNRs is limited by their voltage‐dependent block by extracellular Mg²⁺. High‐frequency afferent stimulation is required to cause sufficient summation of excitatory synaptic potentials (EPSPs) to relieve this block and to permit an influx of Ca²⁺. It has been assumed that this relief of Mg²⁺ block is sufficient for induction. We postulated that the induction of LTP also requires a Src‐dependent plasticity of GluNRs. Using whole‐cell recordings, LTP (GluARs) of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors‐EPSCS was induced by pairing postsynaptic depolarization with presynaptic stimulation. This LTP was both GluNR and Src‐dependent, being sensitive to AP‐5, a GluNR selective antagonist, or to SU6656, a Src‐selective inhibitor. When CNQX was used to block all GluARs, we observed a long‐lasting potentiation of GluNR‐mediated EPSCs. This plasticity was prevented by transiently blocking GluNRs during the induction protocol or by chelating intracellular Ca²⁺. GluNRs plasticity was also prevented by bath applications of SU6656 or intracellular applications of the Src‐selective inhibitory peptide, Src(40–58). It was also blocked by preventing activation of protein kinase C, a kinase that is upstream of Src‐kinase‐dependent regulation of GluNRs. Both GluN2A and GluN2B receptors were found to contribute to the plasticity of GluNRs. The contribution of GluNRs and, in particular, their plasticity to the maintenance of LTP was explored using AP5 and SU6656, respectively. When applied >20 min after induction neither drug influenced the magnitude of LTP. However, when applied immediately after induction, treatment with either drug caused the initial magnitude of LTP to progressively decrease to a sustained phase of reduced amplitude. Collectively, our findings suggest that GluNR plasticity, although not strictly required for induction, is necessary for the maintenance of a nondecrementing component of LTP. © 2010 Wiley‐Liss, Inc.     

Methamphetamine‐induced enhancement of hippocampal long‐term potentiation is modulated by NMDA and GABA receptors in the shell–accumbens

Addictive drugs modulate synaptic transmission in the meso‐corticolimbic system by hijacking normal adaptive forms of experience‐dependent synaptic plasticity. Psychostimulants such as METH have been shown to affect hippocampal synaptic plasticity, albeit with a less understood synaptic mechanism. METH is one of the most addictive drugs that elicit long‐term alterations in the synaptic plasticity in brain areas involved in reinforcement learning and reward processing. Dopamine transporter (DAT) is one of the main targets of METH. As a substrate for DAT, METH decreases dopamine uptake and increases dopamine efflux via the transporter in the target brain regions such as nucleus accumbens (NAc) and hippocampus. Due to cross talk between NAc and hippocampus, stimulation of NAc has been shown to alter hippocampal plasticity. In this study, we tested the hypothesis that manipulation of glutamatergic and GABA‐ergic systems in the shell‐NAc modulates METH‐induced enhancement of long term potentiation (LTP) in the hippocampus. Rats treated with METH (four injections of 5 mg/kg) exhibited enhanced LTP as compared to saline‐treated animals. Intra‐NAc infusion of muscimol (GABA receptor agonist) decreased METH‐induced enhancement of dentate gyrus (DG)‐LTP, while infusion of AP5 (NMDA receptor antagonist) prevented METH‐induced enhancement of LTP. These data support the interpretation that reducing NAc activity can ameliorate METH‐induced hippocampal LTP through a hippocampus‐NAc‐VTA circuit loop. Synapse 70:325–335, 2016 . © 2016 Wiley Periodicals, Inc.     

Transient appearance of Ca2+‐permeable AMPA receptors is crucial for the production of repetitive LTP‐induced synaptic enhancement (RISE) in cultured hippocampal slices

We have previously shown that repetitive induction of long‐term potentiation (LTP) by glutamate (100 μM, 3 min, three times at 24‐hr intervals) provoked long‐lasting synaptic enhancement accompanied by synaptogenesis in rat hippocampal slice cultures, a phenomenon termed RISE (repetitive LTP‐induced synaptic enhancement). Here, we examined the role of Ca²⁺‐permeable (CP) AMPA receptors (AMPARs) in the establishment of RISE. We first found a component sensitive to the Joro‐spider toxin (JSTX), a blocker of CP‐AMPARs, in a field EPSP recorded from CA3‐CA1 synapses at 2–3 days after stimulation, but this component was not found for 9–10 days. We also observed that rectification of AMPAR‐mediated current appeared only 2–3 days after stimulation, using a whole‐cell patch clamp recording from CA1 pyramidal neurons. These findings indicate that CP‐AMPAR is transiently expressed in the developing phase of RISE. The blockade of CP‐AMPARs by JSTX for 24 hr at this developing phase inhibited RISE establishment, accompanied by the loss of small synapses at the ultrastructural level. These results suggest that transiently induced CP‐AMPARs play a critical role in synaptogenesis in the developing phase of long‐lasting hippocampal synaptic plasticity, RISE.     

Lambert–Eaton syndrome antibodies target multiple subunits of voltage‐gated Ca2+ channels

Introduction: Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune presynaptic neuromuscular disorder. Autoantibodies against subunits of voltage‐gated calcium channels (VGCCs) associated with acetylcholine release are thought to cause LEMS. Methods: HEK293 cells expressing specific individual recombinant subunits of α_1A, α_1B, α_1C, and α_1E; β₃; and α₂δ of human neuronal VGCCs were exposed to antibodies from 3 LEMS patients, 1 patient with small‐cell lung carcinoma, and 1 with myasthenia gravis. Results: All LEMS patient antibodies bound to cells containing any of the α₁ or β₃ subunits alone or combined with α₂δ subunits, but not α₂δ alone. Autoantibodies from the patient with small‐cell lung carcinoma but not the myasthenia gravis patient targeted the same VGCC subunits. Conclusions: Autoantibodies from LEMS patients bind directly to multiple VGCC α₁ subunits as well as the β₃ subunit. Thus, multiple components of the presynaptic VGCC complex are prospective targets for antibodies in LEMS. Muscle Nerve 51 : 176–184, 2015     

Repulsive migration of schwann cells induced by slit‐2 through Ca2+‐dependent RhoA‐Myosin signaling

Schwann cells migrate along axons before initiating myelination during development and their migration facilitates peripheral nerve regeneration after injury. Axon guidance molecule Slit‐2 is highly expressed during peripheral development and nerve regeneration; however, whether Slit‐2 regulates the migration of Schwann cells remains a mystery. Here we show that Slit‐2 receptor Robo‐1 and Robo‐2 were highly expressed in Schwann cells in vitro and in vivo. Using three distinct migration assays, we found that Slit‐2 repelled the migration of cultured Schwann cells. Furthermore, frontal application of a Slit‐2 gradient to migrating Schwann cells first caused the collapse of leading front, and then reversed soma translocation of Schwann cells. The repulsive effects of Slit‐2 on Schwann cell migration depended on a Ca²⁺ signaling release from internal stores. Interestingly, in response to Slit‐2 stimulation, the collapse of leading front required the loss of F‐actin and focal adhesion, whereas the subsequent reversal of soma translocation depended on RhoA‐Rock‐Myosin signaling pathways. Taken together, we demonstrate that Slit‐2 repels the migration of cultured Schwann cells through RhoA‐Myosin signaling pathways in a Ca²⁺‐dependent manner.     

Involvement of R‐type Ca2+ channels in neurotransmitter release from spinal dorsolateral funiculus terminals synapsing motoneurons

Molecular studies have revealed the presence of R‐type voltage‐gated Ca²⁺ channels at pre‐ and postsynaptic regions; however, no evidence for the participation of these channels in transmitter release has been presented for the spinal cord. Here we characterize the effects of SNX‐482, a selective R channel blocker, on the monosynaptic excitatory postsynaptic potentials (EPSPs) evoked in motoneurons by stimulation of dorsolateral funiculus (DLF) terminals in a slice preparation from the adult turtle spinal cord. SNX‐482 inhibited neurotransmission in a dose‐dependent manner, with an IC₅₀ of ～9 ± 1 nM. The EPSP time course and membrane time constant of the motoneurons were not altered, suggesting a presynaptic mechanism. The toxin inhibited the residual component of the EPSPs recorded in the presence of N‐ and P/Q‐type Ca²⁺ channel blockers, strongly suggesting a role for the R channels in neurotransmission at the spinal cord DLF terminals. Consistently with this, RT‐PCR analysis of turtle spinal cord segments revealed the expression of the Ca_V2.3 pore‐forming (α_1E) subunit of R channels, whereas the use of anti‐α_1E‐specific antibodies resulted in its localization in the DLF fibers as demonstrated by immunohistochemistry coupled with laser confocal microscopy. J. Comp. Neurol. 513:188–196, 2009. © 2009 Wiley‐Liss, Inc.     

Tumor necrosis factor‐α potentiates long‐term potentiation in the rat dentate gyrus after acute hypoxia

An inadequate supply of oxygen in the brain may lead to an inflammatory response through neuronal and glial cells that can result in neuronal damage. Tumor necrosis factor‐α (TNF‐α) is a proinflammatory cytokine that is released during acute hypoxia and can have neurotoxic or neuroprotective effects in the brain. Both TNF‐α and interleukin‐1β (IL‐1β) have been shown by a number of research groups to alter synaptic scaling and also to inhibit long‐term potentiation (LTP) in the hippocampus when induced by specific high‐frequency stimulation (HFS) protocols. This study examines the effects of TNF‐α on synaptic transmission and plasticity in hippocampal slices after acute hypoxia using two HFS protocols. Field excitatory postsynaptic potentials were elicited in the medial perforant pathway of the dentate gyrus. Exogenous TNF‐α (5 ng/ml) attenuated LTP induced by theta burst stimulation but had no effect on LTP induced by a more prolonged HFS. Pretreatment with lipopolysaccharide (100 ng/ml) or TNF‐α but not IL‐1β (4 ng/ml) prior to a 30‐min hypoxic insult resulted in a significant enhancement of LTP post hypoxia when induced by the HFS. Anti‐TNF, 3,6′‐dithiothalidomide (a TNF‐α synthesis inhibitor), and SB203580 (a p38 MAPK inhibitor) significantly reduced this effect. These results indicate an important modulatory role for elevated TNF‐α levels on LTP in the hippocampus after an acute hypoxic event. © 2015 Wiley Periodicals, Inc.     

Heterotrimeric guanosine triphosphate‐binding protein‐coupled modulatory actions of motilin on K+ channels and postsynaptic γ‐aminobutyric acid receptors in mouse medial vestibular nuclear neurons

Some central nervous system neurons express receptors of gastrointestinal hormones, but their pharmacological actions are not well known. Previous anatomical and unit recording studies suggest that a group of cerebellar Purkinje cells express motilin receptors, and motilin depresses the spike discharges of vestibular nuclear neurons that receive direct cerebellar inhibition in rats or rabbits. Here, by the slice‐patch recording method, we examined the pharmacological actions of motilin on the mouse medial vestibular nuclear neurons (MVNs), which play an important role in the control of ocular reflexes. A small number of MVNs, as well as cerebellar floccular Purkinje cells, were labeled with an anti‐motilin receptor antibody. Bath application of motilin (0.1 μm ) decreased the discharge frequency of spontaneous action potentials in a group of MVNs in a dose‐dependent manner (K_d, 0.03 μm ). The motilin action on spontaneous action potentials was blocked by apamin (100 nm ), a blocker of small‐conductance Ca²⁺‐activated K⁺ channels. Furthermore, motilin enhanced the amplitudes of inhibitory postsynaptic currents (IPSCs) and miniature IPSCs, but did not affect the frequencies of miniature IPSCs. Intracellular application of pertussis toxin (PTx) (0.5 μg/μL) or guanosine triphosphate‐γ‐S (1 mm ) depressed the motilin actions on both action potentials and IPSCs. Only 30% of MVNs examined on slices obtained from wild‐type mice, but none of the GABAergic MVNs that were studied on slices obtained from vesicular γ‐aminobutyric acid transporter‐Venus transgenic mice, showed such a motilin response on action potentials and IPSCs. These findings suggest that motilin could modulate small‐conductance Ca²⁺‐activated K⁺ channels and postsynaptic γ‐aminobutyric acid receptors through heterotrimeric guanosine triphosphate‐binding protein‐coupled receptor in a group of glutamatergic MVNs.     

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.     

Large-conductance Ca2+-activated K+ channel involvement in suppression of cerebral ischemia/reperfusion injury after electroacupuncture atShuigou (GV26) acupoint in rats

Excess activation and expression of large-conductance Ca2+-activated K+ channels (BKCa channels) may be an important mechanism for delayed neuronal death after cerebral ischemia/reperfusion injury. Electroacupuncture can regulate BKCa channels after cerebral ischemia/reperfusion injury, but the precise mechanism remains unclear. In this study, we established a rat model of cerebral ischemia/reperfusion injury. Model rats received electroacupuncture of 1 mA and 2 Hz atShuigou (GV26) for 10 minutes, once every 12 hours for a total of six times in 72 hours. We found that in cerebral ischemia/reperfusion injury rats, ischemic changes in the cerebral cortex were mitigated after electroacupuncture. Moreover, BKCa channel protein and mRNA expression were reduced in the cerebral cortex and neurological function noticeably improved. These changes did not occur after electroacupuncture at a non-acupoint (5 mm lateral to the left side of Shuigou). Thus, our ifndings indicate that electroacupuncture atShuigou improves neurological function in rats following cerebral ischemia/reperfu-sion injury, and may be associated with down-regulation of BKCa channel protein and mRNA expression. Additionally, our results suggest that theShuigou acupoint has functional speciifcity.     

Repeated cocaine exposure decreases dopamine D2‐like receptor modulation of Ca2+ homeostasis in rat nucleus accumbens neurons

The nucleus accumbens (NAc) is a limbic structure in the forebrain that plays a critical role in cognitive function and addiction. Dopamine modulates activity of medium spiny neurons (MSNs) in the NAc. Both dopamine D₁‐like and D₂‐like receptors (including D1R or D_1,5R and D2R or D_2,3,4R, respectively) are thought to play critical roles in cocaine addiction. Our previous studies demonstrated that repeated cocaine exposure (which alters dopamine transmission) decreases excitability of NAc MSNs in cocaine‐sensitized, withdrawn rats. This decrease is characterized by a reduction in voltage‐sensitive Na⁺ currents and high voltage‐activated Ca²⁺ currents, along with increased voltage‐gated K⁺ currents. These changes are associated with enhanced activity in the D1R/cAMP/PKA/protein phosphatase 1 pathway and diminished calcineurin function. Although D1R‐mediated signaling is enhanced by repeated cocaine exposure, little is known whether and how the D2R is implicated in the cocaine‐induced NAc dysfunction. Here, we performed a combined electrophysiological, biochemical, and neuroimaging study that reveals the cocaine‐induced dysregulation of Ca²⁺ homeostasis with involvement of D2R. Our novel findings reveal that D2R stimulation reduced Ca²⁺ influx preferentially via the L‐type Ca²⁺ channels and evoked intracellular Ca²⁺ release, likely via inhibiting the cAMP/PKA cascade, in the NAc MSNs of drug‐free rats. However, repeated cocaine exposure abolished the D₂R effects on modulating Ca²⁺ homeostasis with enhanced PKA activity and led to a decrease in whole‐cell Ca²⁺ influx. These adaptations, which persisted for 21 days during cocaine abstinence, may contribute to the mechanism of cocaine withdrawal. Synapse, 2011. © 2010 Wiley‐Liss, Inc.