High-resolution HLA sequencing and hypocretin receptor 2 autoantibodies in narcolepsy type 1 and type 2.

Narcolepsy is a sleep disorder caused by an apparent degeneration of orexin/hypocretin neurons in the lateral hypothalamic area and a subsequent decrease in orexin/hypocretin levels in the cerebrospinal fluid. Narcolepsy is classified into type 1 (NT1) and type 2 (NT2). While genetic associations in the human leukocyte antigen (HLA) region and candidate autoantibodies have been investigated in NT1 to imply an autoimmune origin, less is known about the pathogenesis in NT2. Twenty-six NT1 and 15 NT2 patients were included, together with control groups of 24 idiopathic hypersomnia (IH) patients and 778 general population participants. High-resolution sequencing was used to determine the alleles, the extended haplotypes, and the genotypes of HLA-DRB3, -DRB4, -DRB5, -DRB1, -DQA1, -DQB1, -DPA1, and -DPB1. Radiobinding assay was used to determine autoantibodies against hypocretin receptor 2 (anti-HCRTR2 autoantibodies). NT1 was associated with HLA-DRB5*01:01:01, -DRB1*15:01:01, -DQA1*01:02:01, -DQB1*06:02:01, -DRB5*01:01:01, -DRB1*15:01:01, -DQA1*01:02:01, -DQB1*06:02:01 (odds ratio [OR]: 9.15; p = 8.31 × 10-4) and HLA-DRB5*01:01:01, -DRB1*15:01:01, -DQA1*01:02:01, -DQB1*06:02:01, -DRB4*01:03:01, -DRB1*04:01:01, -DQA1*03:02//03:03:01, -DQB1*03:01:01 (OR: 23.61; p = 1.58 × 10-4) genotypes. Lower orexin/hypocretin levels were reported in the NT2 subgroup (n = 5) that was associated with the extended HLA-DQB1*06:02:01 haplotype (p = .001). Anti-HCRTR2 autoantibody levels were not different between study groups (p = .8524). We confirmed the previous association of NT1 with HLA-DQB1*06:02:01 extended genotypes. A subgroup of NT2 patients with intermediate orexin/hypocretin levels and association with HLA-DQB1*06:02:01 was identified, indicating a possible overlap between the two distinct narcolepsy subtypes, NT1 and NT2. Low anti-HCRTR2 autoantibody levels suggest that these receptors might not function as autoimmune targets in either NT1 or NT2.

Ion concentrations in cerebrospinal fluid in wakefulness, sleep and sleep deprivation in healthy humans.

Sleep is controlled by a circadian rhythmicity, via a reduction of arousal-promoting neuromodulatory activity, and by accumulation of somnogenic factors in the interstitial fluid of the brain. Recent experiments in mice suggest that a reduced neuronal excitability caused by a reduced concentration of potassium in the brain, concomitant with an increased concentration of calcium and magnesium, constitutes an important mediator of sleep. In the present study, we examined whether such changes in ion concentrations could be detected in the cerebrospinal fluid of healthy humans. Each subject underwent cerebrospinal fluid collection at three occasions in a randomized order: at 15:00 hours-17:00 hours during waking, at 06:00 hours-07:00 hours immediately following 1 night of sleep, and at 06:00 hours-07:00 hours following 1 night of sleep deprivation. When compared with wakefulness, both sleep and sleep deprivation produced the same effect of a small (0.1 mm, about 3%), but robust and highly significant, reduction in potassium concentration. Calcium and magnesium concentrations were unchanged. Our results support a circadian modulation of neuronal excitability in the brain mediated via changes of the interstitial potassium concentration.

Impaired procedural memory in narcolepsy type 1.

OBJECTIVES: Sleep enhances the consolidation of memories. Here, we investigated whether sleep-dependent memory consolidation differs between healthy subjects and narcolepsy type 1 (NT1) patients. MATERIAL AND METHODS: We recruited 18 patients with NT1 and 24 healthy controls. The consolidation of spatial (declarative memory; 2-dimensional object location) and procedural (non-declarative memory; finger sequence tapping) memories was examined across one night of at-home sleep. Sleep was measured by an ambulatory sleep recording device. RESULTS: The overnight gain in the number of correctly recalled sequences in the finger-tapping test was smaller for NT1 patients than healthy subjects (+8.1% vs. +23.8% from pre-sleep learning to post-sleep recall, p = .035). No significant group differences were found for the overnight consolidation of spatial memory. Compared to healthy subjects, the sleep of NT1 patients was significantly more fragmented and shallow. However, no significant correlations were found between sleep parameters and overnight performance changes on the memory tests in the whole group. CONCLUSION: The sleep-dependent consolidation of procedural but not spatial memories may be impaired among patients with NT1. Therefore, future studies are warranted to examine whether sleep improvement, for example, using sodium oxybate, can aid the sleep-dependent formation of procedural memories among NT1 patients.

Actigraphy measurement of physical activity and energy expenditure in narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia: A Sensewear Armband study.

The cause of obesity in narcolepsy type 1 (NT1) patients is not fully understood. The present study investigated if a reduced physical activity could explain weight gain in NT1. Seventy-nine patients were included in this retrospective study and divided into an NT1 group (n = 56) and a non-NT1 group (n = 23), including NT2 and idiopathic hypersomnia (IH). Accelerometry-derived measures of physical activity, total energy expenditure and skin temperature were collected from patients during seven consecutive days without medication. In addition, results from multiple sleep latency tests and the Epworth Sleepiness Scale questionnaire, body weight, height and CSF orexin/hypocretin were acquired. Three measurements of physical activity, including metabolic equivalent of task (MET), the average time of physical activity and step count, were compared without differences between groups. Neither could we find a significant difference in total energy expenditure or skin temperature. Thus, by analysing accelerometric data, we could not find any differences in the amount of physical activity or total energy expenditure explaining overweight in NT1.

Fatigue, insomnia and daytime sleepiness in multiple sclerosis versus narcolepsy.

OBJECTIVES: In multiple sclerosis (MS), fatigue is the most prevalent cause of impaired ability to work. In narcolepsy, daytime sleepiness is the main symptom but some studies indicate fatigue being present. We aimed to assess fatigue and associated features in patients with MS or narcolepsy and healthy controls and to assess whether clinical parameters separate fatigued (MS-F) and non-fatigued MS patients (MS-NoF). MATERIALS & METHODS: In this non-interventional cross-sectional study, we recruited 34 MS patients, 15 narcolepsy type 1 patients and 17 healthy controls. An interviewer administered the Fatigue Severity Scale (FSS), the Insomnia Severity Index (ISI), the Epworth Sleepiness Scale, the Patient Health Questionnaire-9 and the Saltin-Grimby Physical Activity Level Scale. Information about clinical parameters and current treatments was collected. RESULTS: In its fatigue profile, MS-F resembled the narcolepsy group rather than MS-NoF, which resembled the healthy control group. ISI alone was significantly associated with FSS, and only in MS-NoF and healthy controls; in MS-F and the narcolepsy group, no variable was associated with FSS. Months since diagnosis was the only clinical variable significantly separating MS-F from MS-NoF. In MS, disease duration correlated with fatigue. No clinical variables correlated with fatigue in the narcolepsy group. CONCLUSIONS: Fatigued MS patients resemble narcolepsy patients more than they resemble non-fatigued MS patients, who resemble healthy controls. Insomnia is the main factor associated with fatigue in MS, while disease duration is the only clinical variable separating fatigued and non-fatigued MS patients. In fatigued patients, variance in fatigue cannot be explained by insomnia, daytime sleepiness, depression or level of exercise.

The cost utility of pitolisant as narcolepsy treatment.

OBJECTIVES: The cost-effectiveness of available pharmacological treatments for narcolepsy is largely unknown. Available pharmacological treatments are associated with tolerability, abuse, and adherence issues. Pitolisant is the first inverse agonist of the histamine H3 receptor to be prescribed for the treatment of narcolepsy with and without cataplexy. Studies suggest that pitolisant is both as effective as previously introduced drugs and is associated with fewer adverse effects. The objective in this study was to estimate the cost-effectiveness of pitolisant as monotherapy, and pitolisant as an adjunctive treatment to modafinil, compared with standard treatment. MATERIALS & METHODS: Calculations were performed using a Markov model with a 50-year time horizon. Healthcare utilization and quality-adjusted life years (QALYs) for each treatment alternative were calculated assuming no treatment effect on survival. Probabilistic sensitivity analyses were performed for treatment effectiveness and healthcare cost parameters. RESULTS: The cost per additional quality-adjusted life year was estimated at SEK 356 337 (10 SEK ≈ 1 Euro) for pitolisant monotherapy, and at SEK 491 128 for pitolisant as an adjunctive treatment, as compared to standard treatment. The cost-effectiveness measure was demonstrated to be particularly sensitive to the assumptions made concerning indirect effects on total healthcare utilization and the pitolisant treatment cost. CONCLUSIONS: The incremental cost-effectiveness ratios were below the unofficial willingness-to-pay threshold at SEK 500 000. The estimated costs per additional QALY obtained here are likely to overestimate the true cost-effectiveness ratio since significant potential indirect effects-pertaining both to labor-market and household-related productivity-of treatment are not taken into account.

Ionized calcium in human cerebrospinal fluid and its influence on intrinsic and synaptic excitability of hippocampal pyramidal neurons in the rat.

It is well-known that the extracellular concentration of calcium affects neuronal excitability and synaptic transmission. Less is known about the physiological concentration of extracellular calcium in the brain. In electrophysiological brain slice experiments, the artificial cerebrospinal fluid traditionally contains relatively high concentrations of calcium (2-4 mM) to support synaptic transmission and suppress neuronal excitability. Using an ion-selective electrode, we determined the fraction of ionized calcium in healthy human cerebrospinal fluid to 1.0 mM of a total concentration of 1.2 mM (86%). Using patch-clamp and extracellular recordings in the CA1 region in acute slices of rat hippocampus, we then compared the effects of this physiological concentration of calcium with the commonly used 2 mM on neuronal excitability, synaptic transmission, and long-term potentiation (LTP) to examine the magnitude of changes in this range of extracellular calcium. Increasing the total extracellular calcium concentration from 1.2 to 2 mM decreased spontaneous action potential firing, induced a depolarization of the threshold, and increased the rate of both de- and repolarization of the action potential. Evoked synaptic transmission was approximately doubled, with a balanced effect between inhibition and excitation. In 1.2 mM calcium high-frequency stimulation did not result in any LTP, whereas a prominent LTP was observed at 2 or 4 mM calcium. Surprisingly, this inability to induce LTP persisted during blockade of GABAergic inhibition. In conclusion, an increase from the physiological 1.2 mM to 2 mM calcium in the artificial cerebrospinal fluid has striking effects on neuronal excitability, synaptic transmission, and the induction of LTP. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Read the Editorial Highlight for this article on page 435.

Neuromodulation of fast-spiking and non-fast-spiking hippocampal CA1 interneurons by human cerebrospinal fluid.

KEY POINTS: How the brain extracellular fluid influences the activity of GABAergic interneurons in vivo is not known. This issue is examined in the hippocampal brain slice by comparing GABAergic interneuron activity in human versus artificial cerebrospinal fluid. Human cerebrospinal fluid (hCSF) substantially increases the excitability of fast-spiking and non-fast-spiking CA1 interneurons. CA1 pyramidal cells are even more strongly excited by hCSF. The tonic excitation of pyramidal cells, in combination with an increased responsiveness of interneurons to excitatory input, is likely to promote the generation of synchronized network activity in the hippocampus. ABSTRACT: GABAergic interneurons intricately regulate the activity of hippocampal and neocortical networks. Their function in vivo is likely to be tuned by neuromodulatory substances in the brain extracellular fluid. However, in vitro investigations of GABAergic interneuron function do not account for such effects, as neurons are kept in artificial extracellular fluid. To examine the neuromodulatory influence of brain extracellular fluid on GABAergic activity, we recorded from fast-spiking and non-fast-spiking CA1 interneurons, as well as from pyramidal cells, in the presence of human cerebrospinal fluid (hCSF), using a matched artificial cerebrospinal fluid (aCSF) as control. We found that hCSF increased the frequency of spontaneous firing more than twofold in the two groups of interneurons, and more than fourfold in CA1 pyramidal cells. hCSF did not affect the resting membrane potential of CA1 interneurons but caused depolarization in pyramidal cells. The increased excitability of interneurons and pyramidal cells was accompanied by reductions in after-hyperpolarization amplitudes and a left-shift in the frequency-current relationships. Our results suggest that ambient concentrations of neuromodulators in the brain extracellular fluid powerfully influence the excitability of neuronal networks.

Human cerebrospinal fluid increases the excitability of pyramidal neurons in the in vitro brain slice.

KEY POINTS: The cerebrospinal fluid contains numerous neuromodulators at ambient levels but whether, and how, they affect the activity of central neurons is unknown. This study provides experimental evidence that human cerebrospinal fluid (hCSF) increases the excitability of hippocampal and neocortical pyramidal neurons. Hippocampal CA1 pyramidal neurons in hCSF displayed lowered firing thresholds, depolarized resting membrane potentials and reduced input resistance, mimicking properties of pyramidal neurons recorded in vivo. The excitability-increasing effect of hCSF on CA1 pyramidal neurons was entirely occluded by intracellular application of GTPγS, suggesting that neuromodulatory effects were mediated by G-protein coupled receptors. These results indicate that the CSF promotes spontaneous excitatory neuronal activity, and may help to explain observed differences in the activity of pyramidal neurons recorded in vivo and in vitro. The composition of brain extracellular fluid is shaped by a continuous exchange of substances between the cerebrospinal fluid (CSF) and interstitial fluid. The CSF is known to contain a wide range of endogenous neuromodulatory substances, but their collective influence on neuronal activity has been poorly investigated. We show here that replacing artificial CSF (aCSF), routinely used for perfusion of brain slices in vitro, with human CSF (hCSF) powerfully boosts spontaneous firing of CA1, CA3 and layer 5 pyramidal neurons in the rat brain slice. CA1 pyramidal neurons in hCSF display lowered firing thresholds, more depolarized resting membrane potentials and reduced input resistance, mimicking properties of pyramidal neurons recorded in vivo. The increased excitability of CA1 pyramidal neurons was completely occluded by intracellular application of GTPγS, suggesting that endogenous neuromodulators in hCSF act on G-protein coupled receptors to enhance excitability. We found no increase in spontaneous inhibitory synaptic transmission by hCSF, indicating a differential effect on glutamatergic and GABAergic neurons. Our findings highlight a previously unknown function of the CSF in promoting spontaneous excitatory activity, and may help to explain differences observed in the activity of pyramidal neurons recorded in vivo and in vitro.

CSF biomarkers of neurotoxicity in childhood cancer survivors after cranial radiotherapy or surgery.

OBJECTIVE: Treatment of pediatric brain tumors is associated with potential long-term cognitive sequelae. Patients treated with craniospinal irradiation for posterior fossa tumors are at high risk. New biomarkers that could help to differentiate treatment effects from other causes of cognitive dysfunction would be valuable in tailoring optimal survivorship care. Biomarkers that reflect biological mechanisms behind treatment-associated cognitive decline would also be important in the evaluation of future treatment regimens for pediatric brain or skull base tumors. METHODS: In this biomarker-finding study, 10 adult survivors of pediatric medulloblastoma, skull base tumors, and posterior fossa low-grade glioma underwent study specific lumbar puncture at a minimum of 17 years following treatment. We analyzed cerebrospinal fluid biomarkers reflecting neuron and astrocyte integrity, amyloid metabolism, inflammation, extracellular matrix, synaptic integrity, and blood-brain barrier function. The values were compared with biomarker levels in healthy controls of comparable age. RESULTS: Biomarkers reflecting neuronal injury (neurofilament light chain protein), astrocyte injury or activation (glial fibrillary acidic protein) as well as inflammation (YKL-40) were significantly elevated in cancer survivors compared to controls. Biomarkers reflecting amyloid metabolism showed a pattern of decrease in patients treated for medulloblastoma. INTERPRETATION: The results suggest a potential chronic low-grade neurodegeneration and astrocyte activation in patients treated for pediatric brain or skull base tumors. Protein biomarkers of CNS disease could potentially be used to increase our understanding of the contribution from different tumor treatments with regard to long-term symptoms in cancer patients.

Cerebrospinal fluid amyloid precursor protein as a potential biomarker of fatigue in multiple sclerosis: A pilot study.

BACKGROUND: Fatigue is the major cause of disability in MS. Fatigue has been suggested to be primary, part of the neurological disease; it can also be secondary to other diseases outside the CNS or exist as a separate comorbidity. The only forms of measurement currently available are through subjective standardized questionnaires, which are not able to identify primary MS-related fatigue. Therefore, there is a need for objective biomarkers of fatigue in MS. This study explored the viability of 17 possible biomarkers of primary fatigue in MS. Our chosen biomarker panel represents the function and health of different parts of the CNS. METHODS: We evaluated 31 MS patients and 17 healthy controls using the Fatigue Severity Scale (FSS) and Insomnia Severity Index (ISI). We assessed clinical parameters and collected CSF from all participants to analyze 17 biomarkers, some of which in multiple targeted sequences, reflecting structural and functional changes in the brain. Based on FSS scores, MS was divided into MS-Fatigue (MS-F, FSS ≥ 4) and MS-NoFatigue (MS-NoF, FSS < 4). RESULTS: MS-F had significantly lower levels of amyloid precursor protein (APP) peptides than MS-NoF (p = 0.005, p = 0.011). The only biomarker correlating with FSS in any group was APP in MS (r = -0.47, -0.52; p = 0.007, 0.002). APP did not correlate with any clinical parameter in MS but correlated with multiple markers. In MS, FSS correlated with the ISI and months since diagnosis. CONCLUSION: Although the mechanisms remain unknown, altered APP metabolism in MS seems to be associated with fatigue. APP should be evaluated as a biomarker of the role of structural MS pathology in the development of fatigue in individual MS patients.

Quality of life and procrastination in post-H1N1 narcolepsy, sporadic narcolepsy and idiopathic hypersomnia, a Swedish cross-sectional study.

OBJECTIVE/BACKGROUND: A cross-sectional study of health-related quality of life (HRQoL), procrastination and the relation to sleepiness, depression and fatigue in post-H1N1 narcolepsy type 1 (NT1), sporadic NT1 and idiopathic hypersomnia (IH). PATIENTS/METHODS: Participants with NT1 and IH were enrolled from the Department of Neurology, Sahlgrenska University Hospital in Gothenburg (Sweden). All participants completed questionnaires about medication, employment, studies, transfer income, sleepiness, HRQoL, depression, fatigue and three questionnaires for procrastination. RESULTS: Post-H1N1, sporadic NT1 and IH all scored higher than healthy controls on Epworth Sleepiness Scale (ESS), Patient Health Questionnaire (PHQ-9) and Fatigue Severity Scale (FSS), whereas EQ-5D-5L index and VAS was lower than for healthy individuals, but with no difference between groups. Post-H1N1 NT1 had a larger proportion of participants prescribed with sodium oxybate (44% vs. 9%, p = 0.003) and dexamphetamine (62% vs. 17%, p = 0.03) compared to sporadic NT1. The latter also in significantly higher doses than in sporadic NT1 (46 ± 12 vs. 25 ± 10 and 47.5 ± 21 mg, p < 0.0001). Post-H1N1 NT1 also had significantly higher scores on Pure Procrastination Scale (PPS), Irrational Procrastination Scale (IPS) and Susceptibility to Temptation Scale (STS), indicating a higher degree of procrastination. Multivariate analysis showed that depression, and to some extent fatigue, were predictors in NT1 for both HRQoL and procrastination. CONCLUSIONS: The results show that health-related quality of life is impaired and tendency to procrastinate is higher in patients suffering from NT1 and both attributes can in part be explained by depressive symptoms. These findings highlight the impact of symptoms other than sleep and wakefulness regulation in patients with NT1.

Tactile direction discrimination in humans after stroke.

Sensing movements across the skin surface is a complex task for the tactile sensory system, relying on sophisticated cortical processing. Functional MRI has shown that judgements of the direction of tactile stimuli moving across the skin are processed in distributed cortical areas in healthy humans. To further study which brain areas are important for tactile direction discrimination, we performed a lesion study, examining a group of patients with first-time stroke. We measured tactile direction discrimination in 44 patients, bilaterally on the dorsum of the hands and feet, within 2 weeks (acute), and again in 28 patients 3 months after stroke. The 3-month follow-up also included a structural MRI scan for lesion delineation. Fifty-nine healthy participants were examined for normative direction discrimination values. We found abnormal tactile direction discrimination in 29/44 patients in the acute phase, and in 21/28 3 months after stroke. Lesions that included the opercular parietal area 1 of the secondary somatosensory cortex, the dorsolateral prefrontal cortex or the insular cortex were always associated with abnormal tactile direction discrimination, consistent with previous functional MRI results. Abnormal tactile direction discrimination was also present with lesions including white matter and subcortical regions. We have thus delineated cortical, subcortical and white matter areas important for tactile direction discrimination function. The findings also suggest that tactile dysfunction is common following stroke.

Synaptic retrogenesis and amyloid-beta in Alzheimer's disease.

Pathological hallmarks of Alzheimer's disease (AD) include synaptic and neuronal degeneration and the presence of extracellular deposits of amyloid-beta (Abeta) in senile plaques in the cerebral cortex. Although these brain lesions may be seen also in aged non-demented individuals, the increase in brain Abeta is believed by many to represent the earliest event in the disease process. Accumulating evidence suggests that Abeta, which is highly conserved by evolution, may have an important physiological role in synapse elimination during brain development. An intriguing idea is that this putative function can become pathogenic if activated in the aging brain. Here, we review the literature on the possible physiological roles of Abeta and its precursor protein AbetaPP during development with special focus on electrophysiological findings.

Creation of AMPA-silent synapses in the neonatal hippocampus.

In the developing brain, many glutamate synapses have been found to transmit only NMDA receptor-mediated signaling, that is, they are AMPA-silent. This result has been taken to suggest that glutamate synapses are initially AMPA-silent when they are formed, and that AMPA signaling is acquired through activity-dependent synaptic plasticity. The present study on CA3-CA1 synapses in the hippocampus of the neonatal rat suggests that AMPA-silent synapses are created through a form of activity-dependent silencing of AMPA signaling. We found that AMPA signaling, but not NMDA signaling, could be very rapidly silenced by presynaptic electrical stimulation at frequencies commonly used to probe synaptic function (0.05-1 Hz). Although this AMPA silencing required a rise in postsynaptic Ca(2+), it did not require activation of NMDA receptors, metabotropic glutamate receptors or voltage-gated calcium channels. The AMPA silencing, possibly explained by a removal of postsynaptic AMPA receptors, could subsequently be reversed by paired presynaptic and postsynaptic activity.

Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro.

For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling.

Corrigendum: Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro.

[This corrects the article on p. 54 in vol. 10, PMID: 26973467.].

Long-term depression in the developing hippocampus: low induction threshold and synapse nonspecificity.

It was observed that the use of paired-pulse afferent stimulation as test stimulation (0.1-0.02 Hz) in the hippocampal CA1 area in young (1-2 week) rats, but not in older ones, led to declining synaptic activity. We show that such very low-frequency stimulation leads to long-term depression (LTD) initiated by activation of NMDA receptor channels and/or T-type voltage-dependent calcium channels. The depression is initiated within three or four such stimuli, and <10 are sufficient to induce a notable long-term effect. When the paired-pulse stimulation exceeded threshold for postsynaptic spike activation, the depression was preceded by an NMDA receptor-dependent potentiation. Irrespective of whether homosynaptic potentiation or depression occurred, the paired pulse stimulation also induced depression in neighboring synapses alternately activated by single stimuli. These results point to a very high sensitivity for induction of synaptic depression during the neonatal period. They also support the notion that a brief rise in postsynaptic calcium can induce long-term potentiation (LTP) or LTD, a larger rise more likely to induce LTP, as well as that a prolonged modest increase produces selectively only LTD.

Antisecretory factor modulates GABAergic transmission in the rat hippocampus.

Antisecretory Factor (AF) is a protein that has been implicated in the suppression of intestinal hypersecretion and inflammation. Intestinal secretion and inflammation are partly under local and central neural control raising the possibility that AF might exert its action by modulating neural signaling. In the present study we have investigated whether AF can modulate central synaptic transmission. Evoked glutamatergic and GABAergic synaptic transmissions were investigated using extracellular recordings in the CA1 region of hippocampal slices from adult rats. AF (0.5 microg/ml) suppressed GABA(A)-mediated synaptic transmission by about 40% while having no effect on glutamatergic transmission. Per oral administration of cholera toxin as well as feeding of rats with a diet containing hydrothermally processed cereals, known to upregulate endogenous AF plasma activity, mimicked the effect of exogenously administered AF on hippocampal GABAergic transmission. Our results identify AF as a neuromodulator and further raise the possibility that the hippocampus and AF are involved in a gut-brain loop controlling intestinal secretion and inflammation.