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1

Reduction in cholinergic and glutamatergic innervation of ankle extensor but not flexor motoneurons after spinalization calls for selective therapies

100%
Gajewska-Wozniak O.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
Five weeks after spinal cord transection (SCT) at low thoracic segments the number of cholinergic C-terminals, expressing VAChT and glutamatergic terminals of proprioceptive input expressing VGluT1 decreased profoundly on perikarya of soleus α‑motoneurons (Sol Mns). However, their number apposing tibialis anterior (TA) Mns was not affected by SCT. Long‑term locomotor training only partly counteracted deficit in the number of both cholinergic and VGluT1 glutamatergic terminals on Sol Mns. These observations point to high vulnerability of ankle extensor Mns to SCT and sensitivity of both excitatory inputs to the training. These prompted us to apply a selective method of enhancing proprioceptive signaling to ankle extensor Mns. In intact rats 7-days of electrical stimulation of low-threshold proprioceptive afferents in tibial nerve, verified by means of H‑reflex, increased both the number and aggregate volume of cholinergic terminals on Mns of lateral gastrocnemius (LG), a synergist of Sol. It similarly affected proprioceptive glutamatergic innervation of LG Mns. However, this paradigm of activation of LG Mns applied shortly after spinal cord transection did not bring enrichment of their innervation, opening a discussion on optimal parameters of stimulation. FINANCIAL SUPPORT: Supported by grants: National Science Centre 2013/09/B/NZ4/03306, statutory for the Nencki Institute.
2

Locomotor training of spinal rats decreases abundance of GlyR-anchoring gephyrin in the ancle extensor and flexor motoneurons mildly reducing perineuronal nets encapsulating them

51%
Skup M., Glowacka A., Gajewska-Wozniak O., Czarkowska-Bauch J.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: Complete spinal cord transection (SCT) causes reorganization of spinal networks involving changes ofsynaptic terminals abutting on α-motoneurons(MNs).We showed that SCT impoverishes excitatory cholinergic input to ankle extensor but not to flexor MNs and locomotor training leads to its enrichment on both MNs groups (Skup et al. 2012). The opposite effect of training after SCT was found on inhibitory glycinergic (Gly) inputs to MNs. To disclose the impact of SCT and training on postsynaptic components of Gly transmission and on MNs perineuronal nets (PNN), which are inhibitory to synaptic plasticity, and to verify if they respond differently in ankle extensor and flexor MNs. METHODS: GlyR and gephyrin (Geph) were detected immunohistochemically and PNN were visualized with Wisteria floribunda agglutinin (WFA) on sections of L3–6 spinal segments in adult rats 5 weeks after SCT (Th9–10) and after 4 weeks of treadmill training of spinal rats. Extensor and flexor MNs were identified with Diamidine Yellow and Fast Blue respectively, injected intramuscularly. Images acquired in confocal microscope were deconvolved and analyzed with Image-Pro Plus Software. WFA and Geph were quantified in a 3 µm rim around MNs. RESULTS: When all groups of motoneurons were analyzed, no effect of SCT on GlyR and Geph MNs membrane occupancy was detected, but the training decreased GlyR (P<0.05) and Geph (P<0.01) membrane expression to approximately 50% of control. Extensor but not flexor MNs tended to respond to SCT with Geph increase by 22% whereas training decreased it in both to 75%. PNN staining intensity increased after SCT by 75% in extensor and by 44% in flexor MNs (P<0.02) and the training tended to decrease it. CONCLUSIONS: Locomotor training after CST may facilitate reorganization of MN inputs by reducing PNN-encapsulation of MNs and alter MN properties by decreased glycinergic signaling. Supported by grants: NCN 2013/09/B/NZ4/03306, statutory for the Nencki Institute.
3

Enrichment in glutamatergic and cholinergic boutons of ankle extensor alpha-moto neurons after low-threshold stimulation of propriceptive fibres in the adult rat

51%
Gajewska-Wozniak O., Skup M., Czarkowska-Bauch J.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: The effects of low-threshold stimulation of muscle afferents (Ia) on glutamatergic and cholinergic innervation of α-motoneurons (Mns) were tested. Two types of synaptic terminals were analyzed: (1) glutamatergic Ia carrying VGLUT1, contacting monosynaptically Mns; (2) cholinergic C-terminals, carrying VAChT, originating from V0c-interneurons of lamina X, which might receive indirect input from sensory afferents of unknown origin. Our aim wasto clarify whether enhancement of proprioceptive input to ankle extensor Mns, via direct electrical stimulation of Ia afferents in the tibial nerve of awake rats, will affect excitatory innervation of lateral gastrocnemius (LG) Mns. METHODS: LG Mns were identified with True Blue (TB) tracer injected intramuscularly. Tibial nerve was stimulated for 7 days with bursts of 3 pulses (pulse width 200 µs, 4 ms of inter-pulse interval, 25 ms inter-burst interval) in four 20 min sessions daily. The Hoffmann reflex recorded from the soleus muscle, LG synergist, allowed controlling low-threshold stimulation. Proprioceptive Ia glutamatergic and cholinergic C-terminals abutting TB-labeled Mns were detected immunohistochemically on transverse spinalsections, using input-specific anti- VGLUT1 and anti-VAChT antibodies. RESULTS: Confocal analysis revealed that the number of both VGLUT1 and VAChT immunoreactive terminals, contacting the soma and proximal dendrites of LG Mns, increased after stimulation by about 35% and 20%, respectively, comparing to sham-stimulated side (P<0.03, Wilcoxon test). CONCLUSIONS: One week of repetitive low-threshold stimulation of proprioceptive fibers in the tibial nerve enriched glutamatergic and cholinergic innervation of LG Mns indicating that this method might be useful for enhancing an activity of selected group of Mns which are the most vulnerable to the spinal cord injuries (Skup et al. 2012, EJN 36: 2679). Supported by grants: NCN 2013/09/B/NZ4/03306, statutory for the Nencki Institute.
4

Spinal BDNF overexpression leads to opposite effects on glutamatergic ampar and NMDAR than on muscarinic acetylcholine receptor M2 transcript level in rats with complete spinal cord transection

45%
Ji B., Glowacka A., Gajewska-Wozniak O., Czarkowska-Bauch J., Skup M.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Complete spinal cord transection (SCT) disturbs the balance between inhibitory and excitatory inputs to motoneurons increasing their excitability. However SCT causes deficiency in excitatory cholinergic input to ankle extensor motoneurons, whereas brain-derived neurotrophic factor (BDNF) overexpression below the lesion site increases markers of spinal neurotransmission and improves locomotor performance. Because glutamatergic receptors (AMPAR, NMDAR) and muscarinic acetylcholine receptor M2 play a crucial role in motoneuron excitability, we investigated if SCT and BDNF affect their expression. AIM(S): To disclose the impact of SCT and BDNF overexpression on levels of AMPAR, NMDAR and M2 mRNA transcripts 2 weeks after SCT. METHOD(S): Total RNA was isolated from L1-2 and L3-6 spinal fragments after SCT followed by intraspinal injection of PBS (n=6) or AAV-BDNF (n=7). After cDNA transcription, AMPAR (subunits GluR1, GluR2), NMDAR (subunits NR1, NR2A, NR2B), and M2 expression were measured using qRT PCR. RESULTS: In intact rats, GluR2 mRNA level was the highest, followed by NR2A/2B, while NR1 and M2 were the lowest. SCT tended to reduce levels of all mRNA transcripts, except for NR1 which tended to increase in L3-6. BDNF overexpression resulted in a significant increase of NR1 and tendency to increase of NR2A in both spinal fragments, while it led to a significant decrease of M2 in L1-2. CONCLUSIONS: BDNF overexpression slightly upregulated mRNA levels of NMDAR after SCT, not preventing deficits of M2. If M2 mRNA decrease is reflected by M2 protein levels in motoneurons, reduced contribution of M2 in modulation of motoneuron excitability may be postulated. FINANCIAL SUPPORT: 665735-Bio4Med-H2020-MSCA--COFUND-2014; National Science Centre 2013/09/B/ NZ4/03306, statutory for the Nencki Institute. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska‑Curie grant agreement No 665735.
5

Spinal BDNF overexpression partially protects synaptic machinery of neuromuscular junction from disintegration after complete spinal cord transection in adult rats: Neurochemical and morphological changes evaluated by histochemical techniques

45%
Glowacka A., Gajewska-Wozniak O., Bernadzki K. M., Czarkowska-Bauch J., Skup M.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Complete spinal cord transection (SCT) leads to loss of motor control due to disruption of supraspinal tracts and altered functioning of both central and peripheral synapses. We showed that SCT at low thoracic segments causes deficiency in cholinergic input to ankle extensor (soleus) motoneurons, whereas brain-derived neurotrophic factor (BDNF) overexpression below the lesion site increases markers of spinal neurotransmission and improves locomotor performance. These findings raise the question if SCT impairs also integrity of peripheral synapses in soleus muscle and if BDNF can counteract lesion effects. AIM(S): To disclose the impact of SCT and BDNF overexpression on pre- (VAChT and S-100) and postsynaptic (nAChR) components of neuromuscular junction (NMJ) in soleus muscle. METHOD(S): VAChT and S-100 were detected immunohistochemically and acetylcholine receptors were visualized with fluorescently labeled bungarotoxin on free‑floating muscle fibers 2 weeks after SCT and intraspinal injection of PBS (n=6) or BDNF (n=7). Images acquired on Zeiss confocal microscope were deconvoluted with Huygens Professional and analyzed with 3D Imaris Software to evaluate NMJ morphology. RESULTS: SCT reduced the number of contacts of normal morphology to 39% which was accompanied by decrease in NMJs size. BDNF overexpression resulted in preservation of 73% of normal contacts, but did not prevent NMJ shrinkage. VAChT-labeled synaptic vesicles marking motoneuron terminals were visibly more dispersed after SCT than in controls. BDNF did not affect this dispersion. CONCLUSIONS: Spinal BDNF overexpression partially prevents NMJs from denervation, albeit does not counteract the reduced size of NMJ. It needs further investigation whether motor improvement is the effect of direct neuroprotective role of BDNF on NMJs or the result of altered signaling at central synapses. FINANCIAL SUPPORT: National Science Centre 2013/09/B/NZ4/03306, statutory for the Nencki Institute.
6

Early changes in gene expression of spinal perineuronal nets components in rats after complete spinal cord transection

45%
Grycz K., Gajewska-Wozniak O., Ji B., Czarkowska-Bauch J., Skup M.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Perineuronal nets (PNNs), which restrict axonal regeneration in the glial scar and limit synaptic plasticity, are composed of chondroitin sulfate proteoglycans (CSPGs) and Crtl1/Hapln1 link protein essential for PNN formation. Spinal cord transection (SCT) leads to changes of various CSPG proteins differently distributed between 2nd– 8th postlesion weeks. This raises the question if shortly after SCT when glial scar is formed, processes induced by tissue damage alter expression of genes coding for these proteins. AIM(S): To characterize gene expression levels of the selected CSPGs (brevican, neurocan, aggrecan, phosphacan), and of Crtl1/Hapln1 in the spinal cord of the intact rats and to quantify their changes at the second week after SCT at low-thoracic segments. METHOD(S): The CSPGs and Crtl1/Hapln1 gene transcripts were quantified in rats after complete SCT in fragments of the spinal cord: Th 9/10 (lesion site), its vicinity and in L1–L2. To quantify gene expression qRT-PCR was carried out and expression levels were presented relative to internal control gene (GAPDH) as the CT. RESULTS: In intact rats mRNA level of brevican was the highest among all tested CSPGs and Crtl1/Hapln1. Its level exceeded that of neurocan by 5-fold and the rest of CSPGs by at least 10‑fold. SCT caused significant, 4‑fold increase of neurocan and 5-fold decrease of Hapln1 transcripts in the lesion site, comparing to controls, and did not affect phosphacan and brevican transcripts. SCT caused weaker effects in L1–L2 segments where only neurocan and brevican transcripts significantly increased (by 160% and 30% respectively) whereas Crtl1/Hapln‑1 decreased by 40%. CONCLUSIONS: Increased transcript levels of neurocan in the lesion site indicate stimulation of its gene expression in astrocytes. A decrease in Crtl1/Hapln1 transcript may point to potential disturbances in postlesion PNN formation. FINANCIAL SUPPORT: NCN 2013/09/B/NZ4/03306, Preludium (K.G.) and Statutory for the Nencki Institute.
7

Enhancing proprioceptive input to motoneurons differentialy affects expression of neurotrophin 3, BDNF and TrkB/TrkC receptors in rat Hofman-reflex circuitry

45%
Gajewska-Wozniak O., Ziemlinska E., Piotrowska K., Skup M., Czarkowska-Bauch J.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
The importance of neurotrophin 3 (NT-3) for motor control prompted us to ask whether direct low-threshold electrical stimulation of the tibial nerve aimed at activation of Ia fibers, could increase the pool of NT-3 and its receptor TrkC in the Hoffmannreflex circuitry of the soleus (Sol) muscle. The effects were compared with those on BDNF and its TrkB receptor. Cuff-electrode over the tibial nerve was used to deliver continuous bursts of stimuli in awake rats. Functional mapping of neuronal activation with c-Fos showed that a number of spinal neurons was activated by Ia stimuli. Stimulation produced a strong increase of NT-3 protein (ELISA), in L3- 6 spinal segments and in Sol with minor effect on BDNF level in L3-6. Protein level of NT-3 and BDNF corresponded to the changes of NT-3 mRNA and BDNF mRNA expression in L3-6 segments but not in Sol muscle. TrkC and TrkB mRNA tended to decrease in L3-6 but in the Sol muscle TrkB mRNA decreased and TrkC mRNA strongly increased showing sensitization of the Sol muscle to NT-3 signaling. The possibility of increasing NT-3/TrkC signaling in the neuromuscular system, with minor effects on BDNF/TrkB signaling, by selective stimulation of peripheral nerve, which in humans might be applied in non-invasive way, offers an attractive therapeutic tool. Supported by N N 401 0480 33, BIOIMAGINE grants.
8

The impact of training and neurotrophins on functional recovery after complete spinal cord transection: cellular and molecular mechanisms contributing to motor improvement

39%
Skup M., Ziemlinska E., Gajewska-Wozniak O., Platek R., Maciejewska A., Czarkowska-Bauch J.
Acta Neurobiologiae Experimentalis
|
2014
|
tom 74
|
nr 2
Beneficial effects of locomotor training on the functional recovery after complete transection of the spinal cord indicate that in chronic spinal animals spontaneous recovery processes are enhanced and shaped by the training. The mechanisms of that use-dependent improvement are still not fully understood. This review tackles three aspects of this issue: (1) neurochemical attributes of functional improvement showing that concentrations of excitatory and inhibitory amino acids in the lumbar spinal segments, which were changed after transection, normalize after the training, or even raise beyond normal. As it does not translate to functional equilibrium between excitatory and inhibitory neurotransmission and may lead to hyperexcitability, the postsynaptic mechanisms which might be responsible for the hyperexcitability are discussed, including (i) dysfunction of K+-Cl- cotransporter KCC2, which controls the strength and robustness of inhibition, and (ii) altered function of 5-HT2 receptors, which may be targeted to restore KCC2 activity and intrinsic inhibition; (2) morphological changes of lumbar motoneurons and their inputs related to functional improvement of spinal animals, pointing to use-dependent diminution/ reversal of the atrophy of the dendritic tree of the hindlimb motoneurons and of their synaptic impoverishment, which in paraplegic animals differs depending on the degree of disuse of the muscles; (3) the role of neurotrophins in motor improvement of spinal animals showing, that increases in neurotrophins due to training or due to efficient viral vector-based transgene expression, that might be responsible for the enrichment of the dendritic tree, elongation of processes and influence neurotransmitter systems in the areas subjected to plastic modifications after injury, correlate with improvement of locomotor functions.
9

Spinal cord transection leads to attenuation of determinants of GABAergic and glycinergic transmission not accompanied by changes in inhibitory inputs to motoneurons

39%
Ziemlinska E., Maciejewska A., Platek R., Gajewska-Wozniak O., Czarkowska-Banach J., Skup M.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
The data on the responses of inhibitory circuits to the spinal cord transection are conflicting. We examined the segmental distribution of determinants of GABAergic and glycinergic transmission in adult rats five weeks after complete spinal cord transection at Th9-10. Concentrations of the GABA and glycine (Gly) in segments below the lesion were evaluated in rats that did not receive any treatment. Decreases in GABA (24%) and Gly (26%) were found only in the lumbar L1-2 segments. Two other groups of spinal rats received microinjections of PBS (SP-PBS) or AAV- EGFP transgene (SPEGFP) to L1-2. Both led to GABA decrease (43% in L1-2 and 23% in L3-6 segments) and a decrease in mRNA for GAD67 (43% in L1-2 in both groups and 10% in L3-6 segment of SP-PBS vs 49% in L3-6 of SP-EGFP rats). The respective decreases in mRNA for Gly transporter GlyT2 were 68 vs. 72% in L1-2 and 29 vs. 76% in L3-6 segments. These changes were not accompanied by changes in the density of GABAergic/glycinergic network and inputs to motoneurons identified with GAD67/GlyT2 immunostaining. We conclude that albeit spinalization does not reduce inhibitory inputs to lumbar motoneurons it leads to long-term impairment in presynaptic determinants of inhibitory neurotransmission which may attenuate inhibitory signaling. Support: NN401 324739 grant.
10

Long-term effects of subdural injections of an antlerogenic cell homogenate (ACH) in a porcine model of spinal cord injury (SCI)

27%
Wrzosek M., Plonek M., Nicpon J., Chelmonska-Soyta A., Podgorski P., Cegielski M., Gebarowski T., Mietelska-Porowska A., Wojda U., Gajewska-Wozniak O., Skup M.
Acta Neurobiologiae Experimentalis
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2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: The potential use of stem cells in spinal cord regeneration is widely discussed. Xenogenic implantation of antlerogenic stem cell homogenate (ACH) was reported to improve cartilage and cornea regeneration. AIM(S): A multilevel spinal cord reaction assessment to an ACH implantation in a spinal cord injury (SCI) porcine model was undertaken. METHOD(S): ACH (cell line MIC-1; 10×106 cells/ml) was obtained using sonification. Five groups were studied: A-sham, B-negative control, C–E with subdural ACH injection, applied immediately after SCI (C), and 1h (D) and 24 h (E) after SCI. Before (P0), directly after (P1), 2 weeks (P2) and 8 weeks (P3) after contusion, CBC and standard blood biochemistry, TP and CSF pleocytosis, UCHL-1, TNF‑alfa, MBP, IL‑8, IL‑6, IL‑1β in the serum and CSF were compared. The degree of SCI on MRI (1.5T, Philips, Ingenia) and MR-DTI parameters (FA, ADC) were also evaluated. Post-mortem histopathology and IHC labeling for an astroglial (GFAP) and microglial (IBA) reaction were performed. All of the above analyses were double-blind and randomized. RESULTS: The majority of the CSF changes were found only in the late postlesion period (P3). The lack of serum IL‑1β changes during the entire experiment in all animals, together with the HP and IHC findings, point to a lack of pro‑inflammatory reaction to the subdural ACH implantation. Decreased levels of cell degeneration markers (MBP, TNF alfa, IL-8) in the CSF of the animals where ACH was used suggest that it has potential neuroprotective activity. CONCLUSIONS: MR and MR-DTI results and a small astrocyte and microglial response in group C (subdural ACH implantation directly after the SCI), suggest a potential beneficial influence of ACH on the neuronal tissue at the injury site. However, due to the data inhomogeneity, a longer observation on a larger group of animals should be conducted. FINANCIAL SUPPORT: This study was conducted in a National Center for Research and Development project (UOD-DEM-1-352/001) .
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