Association between cystic fibrosis transmembrane regulator genotype and clinical outcomes, glucose homeostasis indices and CF-related diabetes risk in adults with CF.

People living with cystic fibrosis (pwCF) homozygous for F508del present more severe phenotypes. PwCF with compound heterozygous genotypes F508del /A455E and F508del /L206W may have milder cystic fibrosis (CF) phenotypes. We compared F508del homozygotes and common compound heterozygotes (F508del and a second pathogenic variant) in adult patients. Nutritional, pulmonary function and glucose homeostasis indices data were collected from the prospective Montreal CF cohort. Two-hundred and three adults with CF having at least one F508del variant were included. Individuals were divided into subgroups: homozygous F508del/F508del (n=149); F508del/621+1G>T (n=17); F508del/711+1G>T (n=11); F508del/A455E (n=12); and F508del/L206W (n=14). Subgroups with the F508del/L206W and F508del/A455E had a lower proportion with pancreatic exocrine insufficiency (p<0.0001), a higher fat mass (p<0.0001), and lower glucose area under the curve (AUC) (p=0.027). The F508del/L206W subgroup had significantly higher insulin secretion (AUC; p=0.027) and body mass index (p<0.001). Pulmonary function (FEV1) was significantly higher for the F508del/L206W subgroup (p<0.0001). Over a median of 7.37 years, the risk of developing CFRD in 141 patients was similar between groups. PwCF with heterozygous F508del/L206W and F508del/A455E tended to have pancreatic exocrine sufficiency, better nutritional status, improved pulmonary function and better diabetogenic indices, but this does not translate into lower risk of CF-related Diabetes.

Older adults' episodic memory is related to a neurophysiological marker of brain cholinergic activity.

Episodic memory is vulnerable to aging and may be influenced by age-related decline in the neurotransmitter acetylcholine. We probed this relation using a novel, minimally invasive transcranial magnetic stimulation marker of brain acetylcholine: short-latency afferent inhibition (SAI). We used neuropsychological testing to construct a composite score of episodic memory in N = 19 community-dwelling older adults, and stratified older adults into Higher- (N = 9) versus Lower-memory (N = 10) groups before SAI. The Higher-memory group showed significantly stronger SAI than the Lower-memory group, indicating an association between higher brain acetylcholine levels and better episodic memory. The two memory groups were equivalent in the potential confounds of age, education, mood, subjective sleep quality, and executive function. These data converge with others to suggest that episodic memory is related to acetylcholine in older adults. This relation should be further investigated, especially with pharmacology and neuroimaging.

Peak glucose during an oral glucose tolerance test is associated with future diabetes risk in adults with cystic fibrosis.

AIMS/HYPOTHESIS: Cystic fibrosis-related diabetes (CFRD) affects up to 50% of adults with cystic fibrosis (CF) and its presence is associated with adverse effects on nutritional status and pulmonary function. Early diagnosis could minimise CFRD morbidity, yet current methods of an OGTT at 0 and 2 h yield unreliable results. Our aim was to determine which indices from a 2 h OGTT with sampling every 30 min might improve prediction of CFRD. METHODS: Cross-sectional analysis at baseline (n = 293) and observational prospective analysis (n = 185; mean follow-up of 7.5 ± 4.2 years) of the Montreal Cystic Fibrosis Cohort were performed. Blood glucose and insulinaemia OGTT variables were studied in relation to lung function (forced expiratory volume in 1 s [FEV1]), BMI and risk of developing CFRD. RESULTS: At baseline, maximum OGTT glucose (Gmax) was negatively associated with FEV1 (p = 0.003). Other OGTT values, including classical 2 h glucose, were not. A higher Gmax was associated with lower insulin secretory capacity, delayed insulin peak timing and greater pancreatic insufficiency (p < 0.01). Gmax was positively associated with the risk of developing CFRD (p = 0.0029); no individual with a Gmax < 8 mmol/l developed CFRD over the following decade. No OGTT variable correlated to the rate of change in BMI or FEV1. CONCLUSIONS/INTERPRETATION: In adults with CF, Gmax is strongly associated with the risk of developing CFRD; Gmax < 8 mmol/l could identify those at very low risk of future CFRD. Gmax is higher in individuals with pancreatic insufficiency and is associated with poorer insulin secretory capacity and pulmonary function.

Differential effects of the mode of touch, active and passive, on experience-driven plasticity in the S1 cutaneous digit representation of adult macaque monkeys.

This study compared the receptive field (RF) properties and firing rates of neurons in the cutaneous hand representation of primary somatosensory cortex (areas 3b, 1, and 2) of 9 awake, adult macaques that were intensively trained in a texture discrimination task using active touch (fingertips scanned over the surfaces using a single voluntary movement), passive touch (surfaces displaced under the immobile fingertips), or both active and passive touch. Two control monkeys received passive exposure to the same textures in the context of a visual discrimination task. Training and recording extended over 1-2 yr per animal. All neurons had a cutaneous receptive field (RF) that included the tips of the stimulated digits (D3 and/or D4). In area 3b, RFs were largest in monkeys trained with active touch, smallest in those trained with passive touch, and intermediate in those trained with both; i.e., the mode of touch differentially modified the cortical representation of the stimulated fingers. The same trends were seen in areas 1 and 2, but the changes were not significant, possibly because a second experience-driven influence was seen in areas 1 and 2, but not in area 3b: smaller RFs with passive exposure to irrelevant tactile inputs compared with recordings from one naive hemisphere. We suggest that added feedback during active touch and higher cortical firing rates were responsible for the larger RFs with behavioral training; this influence was tempered by periods of more restricted sensory feedback during passive touch training in the active + passive monkeys.NEW & NOTEWORTHY We studied experience-dependent sensory cortical plasticity in relation to tactile discrimination of texture using active and/or passive touch. We showed that neuronal receptive fields in primary somatosensory cortex, especially area 3b, are largest in monkeys trained with active touch, smallest in those trained with passive touch, and intermediate in those trained using both modes of touch. Prolonged, irrelevant tactile input had the opposite influence in areas 1 and 2, favoring smaller receptive fields.

Modulation of the cutaneous and cortical silent period in response to local menthol application.

In this study, we investigated the effects of menthol application on the cortical and cutaneous silent period (CSP/cutSP). Both the cutSP and CSP were assessed while participants (n = 11, young adults) exerted a light contraction with the right thumb. In the 1st block of trials, SPs were measured after the application of a Neutral gel (Aloe Vera) to the dorsal aspect of the hand. In the 2nd block, the same measures were repeated following a Menthol gel (4%) application. Subjective ratings of cooling sensations were obtained for each block. The Neutral gel was consistently perceived as slightly cool by participants, wheres the Menthol gel elicited sensations from cool to very cold. Paired t-tests showed no difference in the cutSP duration between the two conditions, whereas a significant increase in the CSP was detected with the Menthol condition. No correlation was found between changes in the CSP and those of the cutSP. These results highlight the difference between the cutSP and the CSP, as inhibitory phenomena, and point to a cortical contribution to the soothing effects associated with topical menthol applications.

Neurophysiological basis of manual force asymmetries in young and senior adults.

In this study, we investigated age differences in manual force production to explore their neurophysiological basis. Manual pinching and gripping forces were first measured during unilateral and bilateral efforts in two groups of right-handed adults (young, n = 12, senior, n = 11). Then, transcranial magnetic stimulation (TMS) was applied to each hemisphere to assess central motor inhibition via the contralateral and ipsilateral silent period (cSP, iSP). Laterality quotients (LQs) were computed to determine asymmetries for unimanual strength tests and hemispheric asymmetries in TMS measures. Bilateral indices (BLI) were computed to assess the bilateral force deficit (BFD). During unilateral efforts, both young and senior participants exhibited similar degrees of asymmetry. Similarly, no age difference was detected when comparing LQs derived from TMS measures. During bilateral efforts, although BLI tended to be lower in seniors, no age difference was detected. Asymmetry in strength and BLI showed no association with hemispheric asymmetry in TMS measures, except for the asymmetry in pinch strength, which was associated with asymmetry in the iSP duration. These observations confirm that asymmetries in manual strength and BFD are little affected by age. Also, our results show that hemispheric asymmetries in transcallosal inhibition are associated with pinch strength asymmetry.

Short-latency afferent-induced facilitation and inhibition as predictors of thermally induced variations in corticomotor excitability.

Recently (Ansari et al., PeerJ 6:e6163, 2018a; Somatosens Mot Res 35:69-79, 2018b), we showed using transcranial magnetic stimulation (TMS) that focal application of innocuous thermal stimuli to the distal hand produced variable responses in terms of motor-evoked potential (MEP) suppression or enhancement. Here, we sought to investigate possible causes of this variability by examining circuits mediating sensorimotor integration and intra-cortical inhibition. Participants (n = 21) first underwent TMS to assess baseline corticomotor excitability by measuring MEPs at rest with the index finger wrapped in a gel pack at room temperature (24 °C). Then, conditioned protocols were applied to assess short-latency afferent inhibition (SAI), short-latency afferent facilitation (SAF) and short-interval intra-cortical inhibition (SICI). Following baseline measures, MEP modulation in response to distal cooling was recorded with the index finger wrapped in a gel pack at ~ 10 °C. At baseline, participants exhibited variable levels of SAI, SAF and SICI. Participant also exhibited variable responses to cooling with about half of them (11/21) showing suppressed excitability and one-third showing enhanced excitability (7/21). A linear regression analysis revealed that SAI and SAF proved to be good predictors of cooling-induced variations in corticomotor excitability but not SICI. These results provide novel evidence linking variations in SAI and SAF with those in corticomotor excitability elicited in response to focal thermal stimulation, suggesting that these markers could be used to predict responses to sensory stimulation protocols.

Context-dependent tactile texture-sensitivity in monkey M1 and S1 cortex.

Caudal primary motor cortex (M1, area 4) is sensitive to cutaneous inputs, but the extent to which the physical details of complex stimuli are encoded is not known. We investigated the sensitivity of M1 neurons (4 Macaca mulatta monkeys) to textured stimuli (smooth/rough or rough/rougher) during the performance of a texture discrimination task and, for some cells, during a no-task condition (same surfaces; no response). The recordings were made from the hemisphere contralateral to the stimulated digits; the motor response (sensory decision) was made with the nonstimulated arm. Most M1 cells were modulated during surface scanning in the task (88%), but few of these were texture-related (24%). In contrast, 44% of M1 neurons were texture related in the no-task condition. Recordings from the neighboring primary somatosensory cortex (S1), the potential source of texture-related signals to M1, showed that S1 neurons were significantly more likely to be texture related during the task (57 vs 24%) than M1. No difference was observed in the no-task condition (52 vs. 44%). In these recordings, the details about surface texture were relevant for S1 but not for M1. We suggest that tactile inputs to M1 were selectively suppressed when the animals were engaged in the task. S1 was spared these controls, as the same inputs were task-relevant. Taken together, we suggest that the suppressive effects are most likely exerted directly at the level of M1, possibly through the activation of a top-down gating mechanism specific to motor set/intention. NEW & NOTEWORTHY Sensory feedback is important for motor control, but we have little knowledge of the contribution of sensory inputs to M1 discharge during behavior. We showed that M1 neurons signal changes in tactile texture, but mainly outside the context of a texture discrimination task. Tactile inputs to M1 were selectively suppressed during the task because this input was not relevant for the recorded hemisphere, which played no role in generating the discrimination response.

Variations in corticomotor excitability in response to distal focal thermal stimulation.

PURPOSE: This study investigated the effects of thermal stimulation on corticomotor excitability with transcranial magnetic stimulation (TMS). MATERIAL AND METHODS: Participants consisted of healthy young adults (n = 20) and seniors (n = 15). Each experimental session consisted of a baseline (BL) assessment, followed by a warming and a cooling protocol. At BL, recordings of motor evoked potentials (MEPs) and skin temperature were performed with the index finger covered with a 'neutral' gel pack (24 °C). For warming, the same measurements were performed, but with the index covered with a warmed gel pack (45 °C). The gel pack was kept for 5 min, and the measurements were performed at 1 min during warming and 5 and 10 min post. After a break, participants were tested with the cooling protocol (gel pack 10 °C) by repeating the same sequence as in the warming. RESULTS: The two thermal protocols induced the desired range of skin temperatures (warming = 35-45°; cooling = 13-24°). For MEP modulation, the primary analysis revealed no main effects or interactions, owing to the variability of responses to either warming or cooling stimulation. Further analysis of individual responses revealed that modulation, when present, was short-lasting and was characterized by a depression in about half of the participants. Facilitation was also observed, but only in smaller clusters, especially with cooling (13/35). Modulation in MEP amplitude did not correlate with changes in skin temperature. CONCLUSION: These results are consistent with previous reports regarding variability in response to sensory stimulation protocols. In the case of thermal stimulation, such variability likely reflects individual differences in the influences exerted by thermal afferents centrally.

(Lack of) Corticospinal facilitation in association with hand laterality judgments.

In recent years, mental practice strategies have drawn much interest in the field of rehabilitation. One form of mental practice particularly advocated involves judging the laterality of images depicting body parts. Such laterality judgments are thought to rely on implicit motor imagery via mental rotation of one own's limb. In this study, we sought to further characterize the involvement of the primary motor cortex (M1) in hand laterality judgments (HLJ) as performed in the context of an application designed for rehabilitation. To this end, we measured variations in corticospinal excitability in both hemispheres with motor evoked potentials (MEPs) while participants (n = 18, young adults) performed either HLJ or a mental counting task. A third condition (foot observation) provided additional control. We hypothesized that HLJ would lead to a selective MEP facilitation when compared to the other tasks and that this facilitation would be greater on the right than the left hemisphere. Contrary to our predictions, we found no evidence of task effects and hemispheric effects for the HLJ task. Significant task-related MEP facilitation was detected only for the mental counting task. A secondary experiment performed in a subset of participants (n = 6) to further test modulation during HLJ yielded the same results. We interpret the lack of facilitation with HLJ in the light of evidence that participants may rely on alternative strategies when asked to judge laterality when viewing depictions of body parts. The use of visual strategies notably would reduce the need to engage in mental rotation, thus reducing M1 involvement. These results have implications for applications of laterality tasks in the context of the rehabilitation program.

Dopamine modulation of rod pathway signaling by suppression of GABAC feedback to rod-driven depolarizing bipolar cells.

Reducing signal gain in the highly sensitive rod pathway prevents saturation as background light levels increase, allowing the dark-adapted retina to encode stimuli over a range of background luminances. Dopamine release is increased during light adaptation and is generally accepted to suppress rod signaling in light-adapted retinas. However, recent research has suggested that dopamine, acting through D1 receptors, could additionally produce a sensitization of the rod pathway in dim light conditions via gamma-aminobutyric acid (GABA) type C receptors. Here, we evaluated the overall activity of the depolarizing bipolar cell (DBC) population in vivo to ensure the integrity of long-distance network interactions by quantifying the b-wave of the electroretinogram in mice. We showed that dopamine, acting through D1 receptors, reduced the amplitude and sensitivity of rod-driven DBCs during light adaptation by suppressing GABA type A receptor-mediated serial inhibition onto rod DBC GABA type C receptors. Block of D1 receptors did not suppress rod-driven DBC sensitivity when GABAA -mediated serial inhibition was blocked by gabazine, suggesting that the reduction in rod-driven DBC sensitivity in the absence of D1 receptors was due to disinhibition of serial inhibitory GABAergic circuitry rather than a direct facilitatory effect on GABA release onto rod-driven DBC GABA type C receptors. Finally, the large population of GABAergic A17 wide-field amacrine cells known to maintain reciprocal inhibition with rod DBCs could be excluded from the proposed disinhibitory circuit after treatment with 5,7-dihydroxytryptamine.

Multi-Province Listeriosis Outbreak Linked to Contaminated Deli Meat Consumed Primarily in Institutional Settings, Canada, 2008.

A multi-province outbreak of listeriosis occurred in Canada from June to November 2008. Fifty-seven persons were infected with 1 of 3 similar outbreak strains defined by pulsed-field gel electrophoresis, and 24 (42%) individuals died. Forty-one (72%) of 57 individuals were residents of long-term care facilities or hospital inpatients during their exposure period. Descriptive epidemiology, product traceback, and detection of the outbreak strains of Listeria monocytogenes in food samples and the plant environment confirmed delicatessen meat manufactured by one establishment and purchased primarily by institutions was the source of the outbreak. The food safety investigation identified a plant environment conducive to the introduction and proliferation of L. monocytogenes and persistently contaminated with Listeria spp. This outbreak demonstrated the need for improved listeriosis surveillance, strict control of L. monocytogenes in establishments producing ready-to-eat foods, and advice to vulnerable populations and institutions serving these populations regarding which high-risk foods to avoid.

Contribution of retinal ganglion cells to the mouse electroretinogram.

PURPOSE: To quantify the direct contribution of retinal ganglion cells (RGCs) on individual components of the mouse electroretinogram (ERG). METHODS: Dark- and light-adapted ERGs from mice 8 to 12 weeks after optic nerve transection (ONTx, n=14) were analyzed through stimulus response curves for a- and b-waves, oscillatory potentials (OPs), positive and negative scotopic threshold response (p/n STR), and the photopic negative response (PhNR) and compared with unoperated and sham-operated controls, as well as to eyes treated with 6-cyano-7-nitroquinoxaline-2,3-dion (CNQX). RESULTS: We confirmed in mice that CNQX intravitreal injection reduced the scotopic a-wave amplitude at high flash strength, confirming a post-receptoral contribution to the a-wave. We found that ONTx, which is more specific to RGCs, did not affect the a-wave amplitude and implicit time in either photopic or scotopic conditions while the b-wave was reduced. Both the pSTR and nSTR components were reduced in amplitude, with the balance between the two components resulting in a shortening of the nSTR peak implicit time. On the other hand, amplitude of the PhNR was increased while the OPs were minimally affected. CONCLUSION: With an intact a-wave demonstrated following ONTx, we find that the most robust indicators of RGC function in the mouse full-field ERG were the STR components.

Age and hemispheric differences in transcallosal inhibition between motor cortices: an ispsilateral silent period study.

BACKGROUND: In this study, we investigated age and hemispheric differences in transcallosal inhibition (TCI) in the context of active contraction using the ipsilateral silent period (iSP). We also examined whether age-related changes in TCI would be related to corresponding changes in manual performance with age. Participants consisted of right-handed individuals from two age groups (young adults, n=13; seniors, n=17). The iSP was measured for each hemisphere using suprathreshold TMS pulses delivered over the primary motor cortex ipsilateral to the maximally contracting hand while the homologue muscles of the opposite hand were lightly contracting (~15% of the maximum). Manual performance was assessed bilaterally for both grip strength and fine dexterity. RESULTS: Our results yielded two main findings. First, TCI measures derived from iSP were strongly influenced by age, whereas differences between hemispheres were only minor. Second, correlation analyses revealed that age-related variations in TCI measures were related to changes in manual performance, so that left-to-right TCI correlated with right hand performance and vice-versa for the opposite hand/hemisphere. CONCLUSION: Overall, these results concur with other recent reports indicating that mutual inhibition between motor cortices tends to decline with age. In this respect, our observations are in line with the notion that the balance of normally predominantly inhibitory interactions between motor cortices is shifted toward excitatory processes with age.

Voltage-gated sodium channels contribute to the b-wave of the rodent electroretinogram by mediating input to rod bipolar cell GABA(c) receptors.

Voltage-gated sodium (Nav) channels are known to augment cone bipolar cell light responses, increasing the electroretinogram (ERG) b-wave in response to stimulus strengths above the cone threshold. However previous in vivo studies on a number of animal models have not found a role for Nav channels in augmenting the b-wave in scotopic conditions below the cone threshold. We recorded ERGs from mice and rats using a series of TTX concentrations and tested retinal output to ensure complete Nav channel block. We found that TTX concentrations sufficient to completely suppress retinal output caused large (~40%) decrease in the scotopic electroretinogram (ERG) response to high stimulus strengths (1.0 log cd s/m(2)). In addition the b-wave was reduced by ~20% even at stimulus strengths that should predominately excite the rod pathway (-2.2 log cd s/m(2)). Modulating stimulus strength and background luminance showed that Nav channel contribution to the b-wave is strongest in mesopic conditions with low strength stimuli. Blocking GABAc receptors indicted that Nav channels predominately contribute to the b-wave by supporting GABAc input to rod bipolar cells in addition to directly amplifying the light response of cone ON bipolar cells. We also determined that saturating levels of TTX reduced the rat b-wave below cone threshold. Nav channels increase the ERG b-wave in both rod and cone bipolar cell-dominated circuits. In circuits involving rod bipolar cells the effect is mediated indirectly via GABAergic inhibitory cells, while Nav channels directly located on cone bipolar cells amplify light responses in the cone pathways.

Asymmetry in corticomotor facilitation revealed in right-handers in the context of haptic discrimination.

In this study we asked whether asymmetries related to handedness in right-handers (n=10) and left-handers (n=10) could influence hemispheric motor facilitation when the preferred or less-preferred hand is engaged in haptic sensing. Transcranial magnetic stimulation (TMS) was used to assess corticomotor excitability when young participants performed a precision grip under two conditions, i.e., with or without a haptic sensing component. In the grip condition participants were required to grasp a 5-mm thick plate between thumb and index fingers, whereas in the haptic condition they performed the same action but were also required to make judgements about the plate's thickness, i.e., either thin (5 mm) or thick (10 mm). Analysis of task-related variations in motor evoked potentials (MEP) amplitude recorded in hand muscles revealed a significant task×hand/hemisphere interaction only in the group of right-handers when the left hand/right hemisphere was engaged in haptic sensing as opposed to simply gripping. Collectively, these results are congruent with other TMS reports describing a greater degree of hemispheric asymmetry in right-handers, who are typically more strongly lateralised than left-handers. Our results with regard to a rightward hemispheric asymmetry for MEP facilitation with haptic sensing are also congruent with the predominant role ascribed to the right sensorimotor cortex in the processing of proprioceptive information.

Insulinogenic index and early phase insulin secretion predict increased risk of worsening glucose tolerance and of cystic fibrosis-related diabetes.

OBJECTIVE: Measures of stimulated insulin secretion are emerging as important predictors of diabetes mellitus in at-risk populations. We analyzed the utility of clinical estimates of insulin secretion in a prospective cohort at risk for cystic fibrosis-related diabetes (CFRD). METHODS: We divided the profiles of 189 people with CF (pwCF) followed longitudinally in the Montreal CF cohort (mean follow up 6.6 ± 1.2 years) according to quartiles of the insulinogenic index (IGI; (I30-I0)/(G30-G0)); area under the curve for insulin normalized for glucose (AUCins/glu), and HOMA-B at baseline to compare clinical characteristics and risk of CFRD according to quartiles for each measure. We also compared characteristics of 40 pwCF found to have de novo CFRD at baseline. RESULTS: At baseline, IGI and AUCins/glu were lower in subjects with de novo CFRD and those who later developed CFRD than those who never developed CFRD (p < 0.0001 for each). Subjects with the lowest quartiles of IGI, AUCins/glu, and AUCins/glu 0-30 had increased risk of developing CFRD by Kaplan-Meier analysis (p = 0.0244, p = 0.0024, and p = 0.0338, respectively). There was no significant difference in risk between quartiles of HOMA-B. Subjects in the lowest quartile of IGI showed a significant increase in 2-hour OGTT glucose and AUCglu between the initial and final study visits (p = 0.0027 and p = 0.0044, respectively). CONCLUSION: IGI is easily measured in a clinical setting and needs to be validated in prospective studies as a potential tool to improve risk stratification in CFRD with direct relevance to pathogenesis.

Marginal association of fasting blood glucose with the risk of cystic fibrosis-related diabetes.

OBJECTIVES: Cystic fibrosis-related diabetes (CFRD) may be diagnosed by fasting blood glucose ≥ 7.0 mmol/L and/or glucose ≥ 11.1 mmol/L following oral glucose tolerance test (OGTT). We compared the role of fasting and stimulated glucose for diagnosis of CFRD. METHODS: We performed a cross-sectional review of the prevalence of fasting glycemic abnormalities and Kaplan-Meier survival analysis of risk of progression to CFRD according to baseline fasting glucose in the prospective Montreal Cystic Fibrosis Cohort. RESULTS: Isolated fasting hyperglycemia was detected in only 8% of participants at study onset. Eighty percent of subjects had isolated post-challenge hyperglycemia on their first OGTT meeting criteria for CFRD. Kaplan Meier survival analysis demonstrated that impaired fasting glucose (IFG) alone is not a risk factor for CFRD. Subjects with combined IFG and impaired glucose tolerance at baseline (IGT) had the highest risk of progression to CFRD. CONCLUSION: Post-prandial elevations in blood glucose are more common at diagnosis of CFRD. While IGT is a significant risk factor for CFRD, IFG alone is uncommon and does not increase the risk of CFRD. Patients with both IGT and IFG have the highest risk of CFRD.

Functional evidence for D-serine inhibition of non-N-methyl-D-aspartate ionotropic glutamate receptors in retinal neurons.

D-Serine is an important signaling molecule throughout the central nervous system, acting as an N-methyl-D-aspartate (NMDA) receptor coagonist. This study investigated the D-serine modulation of non-NMDA ionotropic glutamate receptors expressed by inner retinal neurons. We first identified that the degradation of endogenous retinal D-serine, by application of D-amino acid oxidase, caused an enhancement of kainate- and α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor-mediated calcium responses from the ganglion cell layer of the isolated rat retina and light-evoked responses obtained by multi-electrode array recordings from the guinea pig retina. Approximately 30-45% of cells were endogenously inhibited by D-serine, as suggested by the effect of D-amino acid oxidase. Conversely, bath application of D-serine caused a reduction in multi-electrode array recorded responses and decreased kainate, but not potassium-induced calcium responses, in a concentration-dependent manner (IC(50), 280 µm). Using cultured retinal ganglion cells to reduce network influences, D-serine reduced kainate-induced calcium responses and AMPA induced whole-cell currents. Finally, the inhibitory effect of D-serine on the kainate-induced calcium response was abolished by IEM 1460, thereby identifying calcium-permeable AMPA receptors as a potential target for D-serine. To our knowledge, this is the first study to address specifically the effect of D-serine on AMPA/kainate receptors in intact central nervous system tissue, to identify its effect on calcium permeable AMPA receptors and to report the endogenous inhibition of AMPA/kainate receptors.

Task-related enhancement in corticomotor excitability during haptic sensing with the contra- or ipsilateral hand in young and senior adults.

BACKGROUND: Haptic sensing with the fingers represents a unique class of manipulative actions, engaging motor, somatosensory and associative areas of the cortex while requiring only minimal forces and relatively simple movement patterns. Using transcranial magnetic stimulation (TMS), we investigated task-related changes in motor evoked potential (MEP) amplitude associated with unimanual haptic sensing in two related experiments. In Experiment I, we contrasted changes in the excitability of the hemisphere controlling the task hand in young and old adults under two trial conditions, i.e. when participants either touched a fine grating (smooth trials) or touched a coarse grating to detect its groove orientation (grating trials). In Experiment II, the same contrast between tasks was performed but with TMS applied over the hemisphere controlling the resting hand, while also addressing hemispheric (right vs. left) and age differences. RESULTS: In Experiment I, a main effect of trial type on MEP amplitude was detected (p = 0.001), MEPs in the task hand being ~50% larger during grating than smooth trials. No interaction with age was detected. Similar results were found for Experiment II, trial type having a large effect on MEP amplitude in the resting hand (p < 0.001) owing to selective increase in MEP size (~2.6 times greater) for grating trials. No interactions with age or side (right vs. left) were detected. CONCLUSIONS: Collectively, these results indicate that adding a haptic component to a simple unilateral finger action can elicit robust corticomotor facilitation not only in the working hemisphere but also in the opposite hemisphere. The fact that this facilitation seems well preserved with age, when task difficulty is adjusted, has some potential clinical implications.