Neuronal Alterations Research Articles

Characterization of the sensory, affective, cognitive, biochemical, and neuronal alterations in a modified chronic constriction injury model of neuropathic pain in mice.

The chronic constriction injury (CCI) of the sciatic nerve is a nerve injury-based model of neuropathic pain (NP). Comorbidities of NP such as depression, anxiety, and cognitive deficits are associated with a functional reorganization of the medial prefrontal cortex (mPFC). Here, we have employed an adapted model of CCI by placing one single loose ligature around the sciatic nerve in mice for investigating the alterations in sensory, motor, affective, and cognitive behavior and in electrophysiological and biochemical properties in the prelimbic division (PrL) of the mPFC. Our adapted model of CCI induced mechanical allodynia, motor, and cognitive impairments and anxiety- and depression-like behavior. In the PrL division of mPFC was observed an increase in GABA and a decrease in d-aspartate levels. Moreover an increase in the activity of neurons responding to mechanical stimulation with an excitation, mPFC (+), and a decrease in those responding with an inhibition, mPFC (-), was found. Altogether these findings demonstrate that a single ligature around the sciatic nerve was able to induce sensory, affective, cognitive, biochemical, and functional alterations already observed in other neuropathic pain models and it may be an appropriate and easily reproducible model for studying neuropathic pain mechanisms and treatments.

Testing alternatives: the use of adipose-derived mesenchymal stem cells to slow neurodegeneration in a rat model of Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disease. Unfortunately, the effectiveness of anti-Parkinson treatments gradually diminishes owing to the progressive degeneration of the dopaminergic terminals. The research described here investigated the effect of adipose-derived mesenchymal stem cells (AD-MSC) versus that of an anti-Parkinson drug in a rat model of Parkinsonism. Forty adult rats were divided into four equal groups, each group receiving a different treatment: vehicle, rotenone, rotenone + AD-MSC, or rotenone + carbidopa/levodopa. Behavioral tests were carried out before and at the end of the treatment and specimens harvested from the midbrain were processed for light and electron microscopy. Genetic expressionof glial fibrillary acidic protein (GFAP) and Nestin mRNA was assessed. Expression of the Lamin-B1 and Vimentin genes was measured, along with plasma levels of Angiopoietin-2 and dopamine. Treatment with rotenone induced pronounced motor deficits, as well as neuronal and glial alterations. The AD-MSC group showed improvements in motor function in the live animals and in the microscopic picture presented by their tissues. The fold change of both genes (GFAP and Nestin) decreased significantly in the AD-MSC and carbidopa/levodopa groups compared to the group with Parkinson's disease. Plasma levels of Angiopoietin-2 and dopamine were significantly increased after treatment (P < 0.001) compared to levels in the rats with Parkinson's disease. AD-MSC reduced neuronal degeneration more efficiently than did the anti-Parkinson drug in a rat model of Parkinsonism.

The Role of the Brain in the Pathogenesis and Physiology of Polycystic Ovary Syndrome (PCOS).

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder, affecting at least 10% of women of reproductive age. PCOS is typically characterized by the presence of at least two of the three cardinal features of hyperandrogenemia (high circulating androgen levels), oligo- or anovulation, and cystic ovaries. Hyperandrogenemia increases the severity of the condition and is driven by increased luteinizing hormone (LH) pulse secretion from the pituitary. Indeed, PCOS women display both elevated mean LH levels, as well as an elevated frequency of LH pulsatile secretion. The abnormally high LH pulse frequency, reflective of a hyperactive gonadotropin-releasing hormone (GnRH) neural circuit, suggests a neuroendocrine basis to either the etiology or phenotype of PCOS. Several studies in preclinical animal models of PCOS have demonstrated alterations in GnRH neurons and their upstream afferent neuronal circuits. Some rodent PCOS models have demonstrated an increase in GnRH neuron activity that correlates with an increase in stimulatory GABAergic innervation and postsynaptic currents onto GnRH neurons. Additional studies have identified robust increases in hypothalamic levels of kisspeptin, another potent stimulator of GnRH neurons. This review outlines the different brain and neuroendocrine changes in the reproductive axis observed in PCOS animal models, discusses how they might contribute to either the etiology or adult phenotype of PCOS, and considers parallel findings in PCOS women.

Distinct gene alterations between Fos‐expressing striatal and thalamic neurons after withdrawal from methamphetamine self‐administration

BackgroundMethamphetamine (Meth) seeking progressively increases after withdrawal (incubation of Meth craving). We previously demonstrated a role of anterior intralaminar nucleus of thalamus (AIT) to dorsomedial striatum (DMS) projections in this incubation. Here, we examined molecular alterations in DMS and AIT neurons activated (identified by neuronal activity marker Fos) during “incubated” Meth‐seeking relapse test after prolonged withdrawal.MethodsWe trained male rats to self‐administer Meth or saline (control condition) for 10 days (6 hr/day). Using fluorescence‐activated cell sorting, we examined gene expression in Fos‐positive (activated during a 2‐hr relapse test) and Fos‐negative (nonactivated) DMS and AIT neurons.ResultsIn DMS, we found increased mRNA expressions of immediate early genes (IEGs) (Arc, Egr1, Npas4, Fosb), Trkb, glutamate receptors subunits (Gria3, Grin1, Grin2b, Grm1), and epigenetic enzymes (Hdac3, Hdac5, Crebbp) in Fos‐positive neurons, compared with Fos‐negative neurons. In AIT, we found that fewer genes (Egr1, Fosb, TrkB, Grin1, and Hdac5) exhibited increased mRNA expression in Fos‐positive neurons. Unexpectedly, in both brain regions, gene alterations described above also occurred in drug‐naïve saline self‐administration control rats.ConclusionsThese results demonstrated that transcriptional regulations in Fos‐positive neurons activated during the relapse tests are brain region‐specific but are not uniquely associated with drug exposure during the self‐administration training.

Simultaneous alterations of oligodendrocyte-specific CNP, astrocyte-specific AQP4 and neuronal NF-L demarcate ischemic tissue after experimental stroke in mice

Ischemic stroke not only affects neurons, but also glial and vascular elements. The development of novel neuroprotective strategies thus requires an improved pathophysiological understanding of ischemia-affected cell types that comprise the ‘neurovascular unit’ (NVU). To explore spatiotemporal alterations of oligodendrocytes, astrocytes and neurons after experimental ischemic stroke, we applied a permanent middle cerebral artery occlusion model in mice for 4 and 24 h. Using fluorescence microscopy, the oligodendrocyte marker 2′,3′-cyclic nucleotide phosphodiesterase (CNP), the neuronal neurofilament light chain (NF-L) and the astroglial aquaporin-4 (AQP4) were analyzed in regional relation to one another.Immunofluorescence intensities of CNP and NF-L were simultaneously increased in the ischemic neocortex and striatum. AQP4 immunoreactivity was decreased in the ischemic striatum, which represents the initial and potentially strongest affected site of infarction. The more distant ischemic neocortex and infarct border zones exhibited areas with alternately increased or decreased AQP4 immunoreactivity, leading to an increase of fluorescence intensity in total.Further, deformed CNP-immunopositive processes were found around axonal spheroids, indicating a combined affection of oligodendrocytes and neurons due to ischemia. Importantly, altered AQP4 immunosignals were not limited to the ischemic core, but were also detectable in penumbral areas. This applies for CNP and NF-L also, since altered immunosignals of all three markers coincided regionally at both time points.In conclusion, the present study provides evidence for a simultaneous affection of oligodendrocytes, astrocytes and neurons after experimental focal cerebral ischemia. Consequently, CNP, AQP4 and NF-L immunofluorescence alterations can be utilized to identify ischemia-affected tissue. The simultaneity of the described alterations further strengthens the concept of interdependent NVU components and distinguishes NF-L, CNP and AQP4 as highly ischemia-sensitive elements. Consequently, future therapeutic approaches might influence stroke evolution via strategies simultaneously addressing both neuronal and glial functions.

Neuronal impairment following chronic Toxoplasma gondii infection is aggravated by intestinal nematode challenge in an IFN-\u03b3-dependent manner

BackgroundIt has become increasingly evident that the immune and nervous systems are closely intertwined, relying on one another during regular homeostatic conditions. Prolonged states of imbalance between neural and immune homeostasis, such as chronic neuroinflammation, are associated with a higher risk for neural damage. Toxoplasma gondii is a highly successful neurotropic parasite causing persistent subclinical neuroinflammation, which is associated with psychiatric and neurodegenerative disorders. Little is known, however, by what means neuroinflammation and the associated neural impairment can be modulated by peripheral inflammatory processes.MethodsExpression of immune and synapse-associated genes was assessed via quantitative real-time PCR to investigate how T. gondii infection-induced chronic neuroinflammation and associated neuronal alterations can be reshaped by a subsequent acute intestinal nematode co-infection. Immune cell subsets were characterized via flow cytometry in the brain of infected mice. Sulfadiazine and interferon-γ-neutralizing antibody were applied to subdue neuroinflammation.ResultsNeuroinflammation induced by T. gondii infection of mice was associated with increased microglia activation, recruitment of immune cells into the brain exhibiting Th1 effector functions, and enhanced production of Th1 and pro-inflammatory molecules (IFN-γ, iNOS, IL-12, TNF, IL-6, and IL-1β) following co-infection with Heligmosomoides polygyrus. The accelerated cerebral Th1 immune response resulted in enhanced T. gondii removal but exacerbated the inflammation-related decrease of synapse-associated gene expression. Synaptic proteins EAAT2 and GABAAα1, which are involved in the excitation/inhibition balance in the CNS, were affected in particular. These synaptic alterations were partially recovered by reducing neuroinflammation indirectly via antiparasitic treatment and especially by application of IFN-γ-neutralizing antibody. Impaired iNOS expression following IFN-γ neutralization directly affected EAAT2 and GABAAα1 signaling, thus contributing to the microglial regulation of neurons. Besides, reduced CD36, TREM2, and C1qa gene expression points toward inflammation induced synaptic pruning as a fundamental mechanism.ConclusionOur results suggest that neuroimmune responses following chronic T. gondii infection can be modulated by acute enteric nematode co-infection. While consecutive co-infection promotes parasite elimination in the CNS, it also adversely affects gene expression of synaptic proteins, via an IFN-γ-dependent manner.

Enriched Environment Shortens the Duration of Action Potentials in Cerebellar Granule Cells.

Environmental enrichment for rodents is known to enhance motor performance. Structural and molecular changes have been reported to be coupled with an enriched environment, but functional alterations of single neurons remain elusive. Here, we compared mice raised under control conditions and an enriched environment. We tested the motor performance on a rotarod and subsequently performed whole-cell patch-clamp recordings in cerebellar slices focusing on granule cells of lobule IX, which is known to receive vestibular input. Mice raised in an enriched environment were able to remain on an accelerating rotarod for a longer period of time. Electrophysiological analyses revealed normal passive properties of granule cells and a functional adaptation to the enriched environment, manifested in faster action potentials (APs) with a higher depolarized voltage threshold and larger AP overshoot. Furthermore, the maximal firing frequency of APs was higher in mice raised in an enriched environment. These data show that enriched environment causes specific alterations in the biophysical properties of neurons. Furthermore, we speculate that the ability of cerebellar granule cells to generate higher firing frequencies improves motor performance.

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings.

Neuronal microtubule (MT) tau protein provides cytoskeleton to neuronal cells and plays a vital role including maintenance of cell shape, intracellular transport, and cell division. Tau hyperphosphorylation mediates MT destabilization resulting in axonopathy and neurotransmitter deficit, and ultimately causing Alzheimer’s disease (AD), a dementing disorder affecting vast geriatric populations worldwide, characterized by the existence of extracellular amyloid plaques and intracellular neurofibrillary tangles in a hyperphosphorylated state. Pre-clinically, streptozotocin stereotaxically mimics the behavioral and biochemical alterations similar to AD associated with tau pathology resulting in MT assembly defects, which proceed neuropathological cascades. Accessible interventions like cholinesterase inhibitors and NMDA antagonist clinically provides only symptomatic relief. Involvement of microtubule stabilizers (MTS) prevents tauopathy particularly by targeting MT oriented cytoskeleton and promotes polymerization of tubulin protein. Multiple in vitro and in vivo research studies have shown that MTS can hold substantial potential for the treatment of AD-related tauopathy dementias through restoration of tau function and axonal transport. Moreover, anti-cancer taxane derivatives and epothiolones may have potential to ameliorate MT destabilization and prevent the neuronal structural and functional alterations associated with tauopathies. Therefore, this current review strictly focuses on exploration of various clinical and pre-clinical features available for AD to understand the neuropathological mechanisms as well as introduce pharmacological interventions associated with MT stabilization. MTS from diverse natural sources continue to be of value in the treatment of cancer, suggesting that these agents have potential to be of interest in the treatment of AD-related tauopathy dementia in the future.

Peripheral Sensitization and Loss of Descending Inhibition Is a Hallmark of Chronic Pruritus

Neurophysiological mechanisms leading to chronicity of pruritus are not yet fully understood and it is not known whether these mechanisms diverge between different underlying diseases of chronic pruritus (CP). This study aimed to detect such mechanisms in CP of various origins. A total of 120 patients with CP of inflammatory origin (atopic dermatitis), neuropathic origin (brachioradial pruritus), and chronic prurigo of nodular type, the latter as a model for chronic scratching, as well as 40 matched healthy controls participated in this study. Stimulation with cowhage induced a more intensive itch sensation compared with stimulation with other substances in all patient groups but not in healthy controls, arguing for sensitization of cutaneous mechano- and heat-sensitive C-fibers in CP. All patient groups showed a decreased intraepidermal nerve fiber density compared with controls. A decreased condition pain modulation effect was observed in all patient groups compared with controls, suggesting a reduced descending inhibitory system in CP. In sum, CP of different etiologies showed a mixed peripheral and central pattern of neuronal alterations, which might contribute to the chronicity of pruritus with no differences between pruritus entities. Our findings may contribute to the development of future treatment strategies targeting these pathomechanisms.

Parvalbumin-positive GABAergic interneurons deficit in the hippocampus in Gunn rats: A possible hyperbilirubinemia-induced animal model of schizophrenia

A reduction of GABAergic markers in postmortem tissue is consistently found in schizophrenia. Importantly, these alterations in GABAergic neurons are not global, which means they are more prevalent among distinct subclasses of interneurons, including those that express the calcium binding protein parvalbumin.A decreased expression of parvalbumin in the hippocampus is a consistent observation not only in postmortem human schizophrenia patients, but also in a diverse number of rodent models of the disease.Meanwhile, previously we reported that the congenital hyperbilirubinemia model rats (Gunn rats), which is a mutant of the Wistar strain, showed behavioral abnormalities, for instance, hyperlocomotor activity, deficits of prepulse inhibition, inappropriate social interaction, impaired recognition memory similar with several rodent models of schizophrenia. Several animal studies linked the importance of palvalbumin in relation to abnormal hippocampal activity and schizophrenia-like behavior.Here, we show that parvalbumin positive cell density was significantly lower in the CA1, CA3 and the total hippocampus of Gunn rats (congenital hyperbilirubinemia model rats) compared to Wistar control rats. The correlations between serum UCB levels and loss of PV expression in the hippocampus were also detected. The decreases in the PV-expression in the hippocampus might suggest an association of the behavioral abnormalities as schizophrenia-like behaviors of Gunn rats, compared to the Wistar control rats.

Halting amyloid-induced dementia

Neuroscience In Alzheimer's disease, amyloid-β accumulation is implicated in the changes in neuronal morphology that underlie cognitive decline. Henderson et al. used a transgenic mouse model for familial Alzheimer's disease. Treating these mice with inhibitors of either the Rho-associated kinase ROCK2 or its downstream serine and threonine kinase target LIMK1 prevented the neuronal morphology alterations subsequently caused by amyloid-β accumulation. Thus, these inhibitors, which are in preclinical or clinical trials for cancer patients, may be prophylactic in individuals at high risk for developing Alzheimer's disease. Sci. Signal. 12 , eaaw9318 (2019).

Effect of Autophagy Modulators on Vascular, Glial, and Neuronal Alterations in the Oxygen-Induced Retinopathy Mouse Model.

Hypoxia is one of the main insults in proliferative retinopathies, leading to neovascularization and neurodegeneration. To maintain homeostasis, neurons require efficient degradation and recycling systems. Autophagy participates in retinal cell death, but it is also a cell survival mechanism. Here, we analyzed the role of autophagy at the three characteristic time periods in the oxygen-induced retinopathy (OIR) mouse model and determined if its modulation can improve vascular and non-vascular alterations. Experiments were performed with chloroquine (CQ) in order to monitor autophagosome accumulation by lysosomal blockade. Post natal day (P)17 OIR mouse retinas showed a significant increase in autophagy flux. In particular, an intense LC3B and p62 staining was observed in inner layers of the retina, mainly proliferating endothelial cells. After a single intraocular injection of Rapamycin at P12 OIR, a decreased neovascular area and vascular endothelial growth factor (VEGF) protein expression were observed at P17 OIR. In addition, whereas the increased expression of glial fibrillary acidic protein (GFAP) was reversed at P26 OIR, the functional alterations persisted. Using a similar therapeutic schedule, we analyzed the effect of anti-VEGF therapy on autophagy flux. Like Rapamycin, VEGF inhibitor treatment not only reduced the amount of neovascular tufts, but also activated autophagy flux at P17 OIR, mainly in ganglion cell layer and inner nuclear layer. Finally, the effects of the disruption of autophagy by Spautin-1, were evaluated at vascular, glial, and neuronal levels. After a single dose of Spautin-1, Western blot analysis showed a significant decrease in LC3B II and p62 protein expression at P13 OIR, returning both autophagy markers to OIR control levels at P17. In addition, neither gliosis nor functional alterations were attenuated. In line with these results, TUNEL staining showed a slight increase in the number of positive cells in the outer nuclear layer at P17 OIR. Overall, our results demonstrate that all treatments of induction or inhibition of the autophagic flux reduced neovascular area but were unable to completely reverse the neuronal damage. Besides, compared to current treatments, rapamycin provides a more promising therapeutic strategy as it reduces both neovascular tufts and persistent gliosis.

Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons.

The crucial step in the pathogenic events that lead to the development and the progression of multiple sclerosis (MS) is the infiltration of autoreactive T cells in the brain. Data from experimental autoimmune encephalomyelitis (EAE) mice indicate that, together with microglia, T cells are responsible for the enhancement of the glutamatergic transmission in central neurons, contributing to glutamate-mediated excitotoxicity, a pathological hallmark of both EAE and MS brains. Here, we addressed the synaptic role of T cells taken from MS patients. A chimeric model of human T cells and murine brain slices was established to record, by Patch Clamp technique, the glutamatergic transmission in the presence of T cells isolated from the peripheral blood of healthy subjects (HS), active (a) and nonactive (na) relapsing remitting MS patients. Intracellular staining and flow cytometry were used to assess tumour necrosis factor (TNF) expression in T cells. Chimeric experiments indicated that, compared to HS and naMS, T cells from aMS induced an increase in glutamatergic kinetic properties of striatal neurons. Such alteration, reminiscent of the those induced by EAE T cells, was blocked by incubation of the slices with etanercept, a TNF receptor antagonist. Of note, T cells from aMS expressed more TNF than naMS patients and HS subjects. These data highlight the synaptotoxic potential retained by MS T cells, suggesting that during the inflammatory phase of the disease infiltrating T cells could influence the neuronal activity contributing to the TNF-mediated mechanisms of glutamate excitotoxicity in central neurons.

Subchronic cerebrolysin treatment alleviates cognitive impairments and dendritic arborization alterations of granular neurons in the hippocampal dentate gyrus of rats with temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is one of the most frequent forms of focal epilepsy; patients with this condition, in addition to exhibiting complex seizures, also exhibit cognitive deficits. In the temporal lobe, the hippocampus, a structure relevant to learning and memory processes, is particularly affected by epilepsy. In animal models of TLE induced by pilocarpine, learning and memory deficiencies associated with changes in synaptic plasticity of the hippocampus have been reported. Cerebrolysin (CBL) is a biologically active mixture of low molecular weight peptides with neuroprotective and neurotrophic effects. The objective of the present study was to determine whether subchronic CBL treatment of rats in the chronic phase of TLE reduces the number and intensity of seizures, and whether CBL treatment can improve cognitive deficits (learning and spatial memory) and dendritic morphology in granular dentate neurons of the hippocampus. Temporal lobe epilepsy (lithium–pilocarpine model) was induced in male Wistar rats (weight, 250–300 g). Two epileptic groups were studied, in which CBL (538 mg/kg) or vehicle was administered intraperitoneally for 5 consecutive days per week for 3 weeks. Respective controls were also included in the study. At the end of treatment, the Barnes maze test (BMT) was used to assess spatial navigational learning and memory. The dendritic morphology of the dentate gyrus was also evaluated using the Golgi–Cox staining method. Results of this study did not support an antiepileptic effect of CBL. Epileptic animals treated with this agent exhibited secondarily generalized seizures similar in frequency and intensity to those of epileptic animals treated only with vehicle. However, when analyzing dendritic morphology of hippocampal granular neurons in these animals, CBL appeared to attenuate dendritic deterioration caused by epilepsy, which was associated with improved cognitive performance of the CBL-treated animals in the BMT compared with vehicle-treated epileptic rats. In conclusion, although CBL did not exert an anticonvulsant effect against secondarily generalized seizures, it can be proposed for use as an add-on therapy in epilepsy management to prevent neuronal alterations, and to improve memory and learning processes.

Study molecular of interaction between N,N-dimethyltryptamine analogs (DMT) with 5-HT1A and 5-HT1B receptors, associated in neuronal alterations

Study molecular of interaction between N,N-dimethyltryptamine analogs (DMT) with 5-HT1A and 5-HT1B receptors, associated in neuronal alterations

Ventrolateral Periaqueductal Gray Matter Neurochemical Lesion Facilitates Epileptogenesis and Enhances Pain Sensitivity in Epileptic Rats

The ventrolateral periaqueductal gray matter (vlPAG) plays a critical role in the pathogenesis of migraine and few studies have shown that vlPAG might be involved in the pathophysiology of epilepsy. But its roles in epileptogenesis and comorbid relationship between migraine and epilepsy have never been reported. In this study, the impairments of vlPAG neuronal network during spontaneous recurrent seizure (SRS) development after status epilepticus (SE) were investigated, and the pain sensitivity as well as the SRS investigated after neurochemical lesion to vlPAG to determine the role of vlPAG in epileptogenesis and in migraine comorbidity with epilepsy. Neuronal loss and alterations of excitatory and inhibitory neural transmission within vlPAG accompanied the development of epileptogenesis induced by SE. On the other hand, neurochemical lesion to vlPAG enhanced frequency and duration of spontaneous seizure event and frequency of epileptiform inter-ictal spike discharges in electroencephalography (EEG), but decreased pain threshold in epileptic rats. This indicates an involvement of the pain regulating structure, vlPAG, in the pathogenesis of epilepsy. This may imply that vlPAG network alterations could be a possible underlying mechanism of the interactive comorbid relationship between epilepsy and migraine.

Structural and Functional Abnormalities in the Olfactory System of Fragile X Syndrome Models.

Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability. It is produced by mutation of the Fmr1 gene that encodes for the Fragile Mental Retardation Protein (FMRP), an important RNA-binding protein that regulates the expression of multiple proteins located in neuronal synapses. Individuals with FXS exhibit abnormal sensory information processing frequently leading to hypersensitivity across sensory modalities and consequently a wide array of behavioral symptoms. Insects and mammals engage primarily their sense of smell to create proper representations of the external world and guide adequate decision-making processes. This feature in combination with the exquisitely organized neuronal circuits found throughout the olfactory system (OS) and the wide expression of FMRP in brain regions that process olfactory information makes it an ideal model to study sensory alterations in FXS models. In the last decade several groups have taken advantage of these features and have used the OS of fruit fly and rodents to understand neuronal alteration giving rise to sensory perception issues. In this review article, we will discuss molecular, morphological and physiological aspects of the olfactory information processing in FXS models. We will highlight the decreased inhibitory/excitatory synaptic balance and the diminished synaptic plasticity found in this system resulting in behavioral alteration of individuals in the presence of odorant stimuli.

Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington's disease.

A disintegrine and metalloproteinase 10 (ADAM10) is implicated in synaptic function through its interaction with postsynaptic receptors and adhesion molecules. Here, we report that levels of active ADAM10 are increased in Huntington's disease (HD) mouse cortices and striata and in human postmortem caudate. We show that, in the presence of polyglutamine-expanded (polyQ-expanded) huntingtin (HTT), ADAM10 accumulates at the postsynaptic densities (PSDs) and causes excessive cleavage of the synaptic protein N-cadherin (N-CAD). This aberrant phenotype is also detected in neurons from HD patients where it can be reverted by selective silencing of mutant HTT. Consistently, ex vivo delivery of an ADAM10 synthetic inhibitor reduces N-CAD proteolysis and corrects electrophysiological alterations in striatal medium-sized spiny neurons (MSNs) of 2 HD mouse models. Moreover, we show that heterozygous conditional deletion of ADAM10 or delivery of a competitive TAT-Pro-ADAM10709-729 peptide in R6/2 mice prevents N-CAD proteolysis and ameliorates cognitive deficits in the mice. Reduction in synapse loss was also found in R6/2 mice conditionally deleted for ADAM10. Taken together, these results point to a detrimental role of hyperactive ADAM10 at the HD synapse and provide preclinical evidence of the therapeutic potential of ADAM10 inhibition in HD.

Morphological and neurochemical plasticity of rat mesencephalic trigeminal neurons

The mesencephalic trigeminal nucleus (Me5) is a unique structure in the central nervous system (CNS), made up of pseudounipolar sensory neurons. It is also a suitable paradigm for studying the plastic alterations in neurons. It is known that the Me5 neurons utilize various neurotransmitters under normal conditions, though little information is available about the morphological and chemical events taking place in the nucleus after injury. This review provides concise description of the structural adaptive changes in Me5 neurons following peripheral axotomy of the masseteric nerve. Furthermore, it validates NADPH-diaphorase activity in them, and using immunohistochemistry for glutamate (Glu), substance P (SP), calcitonin-gene related protein (CGRP), neuropeptide tyrosine (NPY) and galanin (GAL), it deals with the altered neurochemical phenotype of the injured neurons. Our results distinctly show that the Me5 neurons in the rat are extremely sensitive to peripheral injury and we demonstrate their distinct structural and neurochemical plasticity. The adaptive morphological alterations comprise of both qualitative and quantitative alterations in the axotomized Me5 population which are statistically significant when compared with the number and phenotype of the neurons on the contralateral intact side. Besides, the axotomy-induced alterations in the neurochemical character of Me5 are best signified by the down-regulation of the classical neurotransmitters under normal conditions, and the up-regulation of nitric oxide synthase and de novo synthesis of certain neuroactive substances such as NPY, SP, GAL and VIP. It can be inferred that the described phenomena only occur in the nucleus in cases of injury and changes in the environmental cues, and serve as adaptive mechanisms and powerful trophic factors for the neuronal survival in the Me5. There is, undoubtedly, still a long way to go in order to clarify the dynamic and plastic alterations occurring in the CNS in health and disease, and also explain their role in such important functions as pain, perception, learning, cognition and memory.

Effects of post-weaning social isolation on social behaviors and oxytocinergic activity in male and female rats

AimsPost-weaning social deprivation is known to induce behavioral and neuronal alterations associated with anxiety and stress responses in adulthood. However, the effects of social deprivation on the development of sociability are poorly understood. We examined the effects of social deprivation on subsequent social behaviors and oxytocinergic activity using socially-isolated (approximately two months post-weaning) male and female rats. Main methodsThe behaviors were analyzed using a social preference test and a social approach test. Immunohistochemical investigations were conducted in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) to examine the effects of social isolation on oxytocinergic activity in these regions. Oxytocinergic activity was measured by quantifying the number of oxytocin neurons expressing Fos following exposure to a novel conspecific. In all of the experiments of this study, ovariectomized females were used for social stimuli. Key findingsThe behavioral results show that isolation-reared females, but not males, displayed impaired social preference and decreased social approach towards ovariectomized females, compared with the pair-reared group, suggesting low priority of processing social versus non-social stimuli and low motivation for contact with a stranger, respectively. The immunohistochemical results show that social isolation decreased both the number and the ratio of Fos-positive cells in oxytocin neurons in the PVN in females, but not in males, following exposure to ovariectomized females. In the SON, the Fos-positive ratio was decreased in isolation-reared females, but not in males, compared with the pair-reared group. SignificancePost-weaning social isolation changed social behaviors and oxytocinergic activity in female rats, suggesting that in female rats post-weaning social experiences contribute to the development of sociability. These findings could impact the treatment of social dysfunction in humans.