In vivo synaptic transmission in the zebra finch high vocal center and robust nucleus of the arcopallium after different stimulus patterns

BACKGROUND： Electrophysiological studies using brain slices have revealed that the developmental regulation of synaptic plasticity in vocal learning pathway is essential for song learning in zebra finches. Publications reporting in vivo electrophysiological investigation are scarce. Many aspects of neural mechanisms underlying song learning and production still remain uncertain. OBJECTIVE： To observe the efficacy of paired pulses and the effect on synaptic transmission induced by low-frequency stimulations, high-frequency stimulations, and theta-burst stimulations. DESIGN, TIME AND SETTING： A comparative observation. The experiment was conducted from October 2006 to October 2007 in the Neurophysiology Laboratory of South-China Normal University. MATERIALS： Twenty-four adult male zebra finches were supplied by the Department of Animal Experiment of College of Life Sciences, South China Normal University. A SEN-7203 stimulator （NIHON KOHDEN）, as well as a DSJ-731WF microelectrode amplifier and DSJ-F amplifier （provided by South-China Normal University）, were used to stimulate and record, respectively. METHODS： Animals were randomly divided into low-frequency, high-frequency, and theta-burst frequency stimulation groups. After recording evoked potentials, an input-output curve was evaluated. Subsequently, the efficacy of paired pulses with different stimulus intensity （1/3, 1/2, 2/3, or 3/4 of the value that induced the largest synaptic response）, as well as interpulse intervals （50, 75, and 100 ms）, was measured in each group. The test stimulus intensity was set to a level that evoked 1/2 or 1/3 amplitude of the maximum response. MAIN OUTCOME MEASURES： Changes in amplitude, slope, and area of evoked potentials elicited by different stimulus patterns. RESULTS： （1） Efficacy of paired pulses： there was significant paired-pulse facilitation in the high vocal center and robust nucleus of the arcopallium （HVC-RA） synapse. Efficacy decreased when paired-pulse intervals or stimulus intensities were increased. （2） Low-frequency stimulations at 1 Hz had a negligible effect on efficacy of synaptic transmission, while 5 Hz depressed synaptic transmission for only 5 minutes. （3） High-frequency stimulations at 50 Hz or 100 Hz induced synaptic depression that lasted for up to 30 minutes. （4） Theta-burst stimulation depressed synaptic transmission efficiency significantly for about 10 minutes. However, in contrast to low-frequency or high-frequency stimulations, theta-burst stimulations also induced slight potentiation of synaptic transmission for up to 60 minutes following depression phase, although the slope or area did not change. CONCLUSION： Paired pulses induced a remarkable efficacy of paired pulses in the high vocal center and robust nucleus of the arcopallium pathway. Low-frequency, high-frequency, or theta-burst frequency stimulation did not induce long-lasting changes in synaptic transmission.

Effects of diazepam on glutamatergic synaptic transmission in the hippocampal CA1 area of rats with traumatic brain injury

The activity of the Schaffer collaterals of hippocampal CA3 neurons and hippocampal CA1 neurons has been shown to increase after lfuid percussion injury. Diazepam can inhibit the hy-perexcitability of rat hippocampal neurons after injury, but the mechanism by which it affects excitatory synaptic transmission remains poorly understood. Our results showed that diazepam treatment signiifcantly increased the slope of input-output curves in rat neurons after lfuid per-cussion injury. Diazepam signiifcantly decreased the numbers of spikes evoked by super stimuli in the presence of 15 μmol/L bicuculline, indicating the existence of inhibitory pathways in the injured rat hippocampus. Diazepam effectively increased the paired-pulse facilitation ratio in the hippocampal CA1 region following fluid percussion injury, reduced miniature excitatory postsynaptic potentials, decreased action-potential-dependent glutamine release, and reversed spontaneous glutamine release. These data suggest that diazepam could decrease the lfuid per-cussion injury-induced enhancement of excitatory synaptic transmission in the rat hippocampal CA1 area.

Effect of electroacupuncture on synaptic transmission in dentate gyrus of the hippocampus in cerebral ischemic injured rats

BACKGROUND： Some studies suggest that the long-term potentiation （LTP） of synaptic transmission may be the basis for the neural synaptic plasticity of hippocampus, but can be evoked by various factors including electroacupuncture. OBJECTIVE： To observe the effect of electroacupuncture on the activities of basic synaptic transmission in dentate gyrus of hippocampus and the changes of high frequency stimulation （HFS） induced activity of synaptic transmission in cerebral ischemic injured rats. DESIGN： A randomized control trial.SETTING： Shenzhen Hospital of Traditional Chinese Medicine affiliated to Guangzhou University of Traditional Chinese Medicine. MATERIALS： Sixty healthy male Wistar rats, weighing 150-250 g, were provided by the Experimental Animal Center of Guangzhou University of Traditional Chinese Medicine. The experiment began after adaptation of environment for 1 week under standard experimental environment. The main experimental instruments included the programming electrical acupuncture apparatus （PCEA, product of the Institute of Acupuncture and Meridians, Anhui College of Traditional Chinese Medicine） and multichannel physiologic recorder （RM-86, Nihon Konden）. METHODS： The experiment was carried out in Guangzhou University of Traditional Chinese Medicine between July 2003 and July 2004. ①Embedding of brain electrodes： In reference of the Pellegrino＇s rat brain atlas, the bipolar electrode stimulator was embedded into the perforant path （PP） anterior to the entorhinal area with location coordinates of AP 7.5 mm, L 4.2 mm and H 3.0 mm, that is, 7.5 mm posterior to the anterior fontanelle, 4.2 mm laterally on the right side and 3.0 mm under the subcortex. The subcortex recorder electrode coordinates are AP 3.8 mm, L 2.5 mm and H 3.5 mm, located in the granular cell layer of the unilateral dentate gyrus （DG） of hippocampus, at the site of which an opening with the diameter of 1.5 mm was drilled for the purpose of embedding of the stimulating and recording electrodes, and at the site by mild adjusting the positions of these electrodes where maximal population spike （PS） was recorded, fastened the electrodes at last. ② The 60 rats were randomized into two major groups, namely, fundamental stimulation （FS） group （basic group） and high frequency stimulation （HFS） group. Each group was further divided into three subgroups respectively： Sham-operated subgroup （n=10）： only exposed bilateral common carotid arteries without blocking their blood flow; Cerebral ischemia model subgroup （n=10）： exposing bilateral common carotid arteries and blocking their blood flow; Ischemia plus electroacupuncture subgroup （n=10）： blocked blood flow of bilateral common carotid arteries and received electroacupuncture. The electroacupuncture acupoints were the points of Du meridian, including Baihui （GV20）, Dazhui （GV14）, and points of Pen meridian, including Qihai （CV6） and Guanyuan （CV4）. ③ Process of electroacupuncture： All the rats underwent testing stimulation （1/30 Hz frequency and 0.1 ms breadth） at 30 minutes before modeling, PS values were recorded as the indexes of the excitation of DG granular cell population, and the data were input to computer for data analysis. During the experiment, the intensity of stimulation was kept stable by adopting 1/2 the value of stimulation intensity that could induce maximal PS amplitude. In the basic group, PS were recorded for 120 minutes after modeling, and among the rats in the electroacupuncture group, PS was recorded at 10 minutes before and 60 minutes after blocking blood flow in the carotid artery during continuous electrical acupuncture. In the HFS group, HFS was given immediately after modeling, PS were recorded for 180 minutes at 10 minutes after HFS was given in the sham-operated group and model group, rats in the electroacupuncture group were treated with electroacupuncture for 60 minutes at 30 minutes after HFS was given, and PS was recorded for 180 minutes after 10 minutes. LTP was triggered by HFS and PS values were determined and recorded through measuring stimulations respectively 0, 10, 30, 60, 120 and 180 minutes after the evokes.④ Methods for expressing the level of synaptic transmission： Each testing stimulus provoked one PS, and 10 successive amplitude values （V/mV） were averaged relevant to a certain time cut. The averaged PS of 6 time cuts at 30 minutes before modeling was made as basal synaptic transmission level as control. Synaptic transmission at each time cut was expressed as： p=（ Vdifferentime cut / Vbasal） × 100%. MAIN OUTCOME MEASURES： The differences of synaptic transmission level were compared among the subgroups in the basic group after models also among the subgroups in the HFS group after HFS.RESULTS： All the 60 rats were involved in the analysis of results. ① Comparison of synaptic transmission level at different time cut after modeling and the effect of electroacupuncture in the subgroups of the basic group： The synaptic transmission level in the sham-operated subgroup had no significant change within 120 minutes （P 〉 0.05）. The synaptic transmission levels at 10, 30 and 60 minutes in the model subgroup were obviously lower than those in the sham-operated group [（60±7）%, （90±3）%, （93±4）%; （100±5）%, （102±6）%, （105±7）%, P 〈 0.05-0.01]. With the prolongation of time for ischemia/reperfusion, the synaptic transmission level gradually ascended to the normal level, and those at 90 and 120 minutes were close to those in the sham-operated group （P 〉 0.05）. In the subgroup of electroacupuncture, the synaptic transmission levels at 10, 30, 60, 90 and 120 minutes were obviously higher than those in the model subgroup [（93±5）%, （106±10）%, （123±16）%, （145±20）%, （168±25）%; （96±7）%, （98±8）%, P 〈 0.05-0.01].② Comparison of synaptic transmission level at different time cut after HFS and the effect of electroacupuncture in the groups： In the sham-operated group, the synaptic transmission level after HFS increased significantly, and maintained without decrease within 180 minutes. In the model group, the synaptic transmission level at 0, 10, 30, 60, 120 and 180 minutes after HFS were obviously lower than those in the sham-operated group [（60±7）%, （95±9）%, （138±11）%, （141±13）%, （140±13）%, （138±15）%; （100±6）%, （182±21）%, （179±18）%, （177±18）%, （175±23）%, （178±24）%, P 〈 0.01]. The synaptic transmission level at 60, 120 and 180 minutes after HFS in the electroacupuncture group were close to those in the sham-operated group （P 〉 0.05）, those at 120 and 180 minutes after HFS in the electroacupuncture group were obviously higher than those in the model group [（171±22）%, （181±25）%, P 〈 0.05-0.01]. CONCLUSION： Electroacupuncture could enhance the basic activity of synaptic transmission in the dentate gyros of hippocampus in cerebral ischemic injury in rats. Electroacupuncture has obvious LTP effect on the activity of synaptic transmission induced by HFS.

Insulin Age-Dependently Modulates Synaptic Transmission and AMPA Receptor Trafficking in Region CA1 of the Rat Hippocampus

Insulin induces long-term depression (insulin-LTD) in the CA1 region of the rat juvenile hippocampus. This insulin-LTD may be due in part to internalization of the GluA2 subunit of the AMPA receptor (AMPAR) events that haven’t been studied in the mature rat hippocampus. In our studies, we used hippocampal preparations from juvenile (14 - 25 days) and mature (60 - 90 days) rats to assess insulin modulation of CA1 synaptic transmission and AMPAR trafficking and phosphorylation. Using field potential electrophysiology, we observed that insulin induced LTD in the juvenile hippocampus (as previously reported) in the presence and absence of phosphoinositide 3-kinase (PI3K) activity, but produced no significant long-term changes in the mature hippocampus in the presence of PI3K activity. Interestingly, during PI3K inhibition, insulin did produce LTD in the mature hippocampus. Additionally, insulin induced a long-term decrease in plasma membrane expression of the GluA2 and GluA1 subunits of the AMPAR in the juvenile, but not mature hippocampus. Furthermore, there was a long-term decrease in GluA1 phosphorylation at Serine 845 in the juvenile, but not mature hippocampus. These data reveal that insulin modulation of synaptic plasticity and AMPAR modulation within the hippocampus is age-dependent, suggesting that insulin-regulated behaviors may also show age-dependence. These findings are important largely due to the increased use of insulin as a therapeutic throughout the lifespan. Our data suggest that additional work should be done to determine how this use of insulin throughout different stages of life might affect synaptic function and development.

Gestational dexamethasone exposure impacts hippocampal excitatory synaptic transmission and learning and memory function with transgenerational effects

The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons.Here we explored how gestational exposure to dexamethasone,a synthetic glucocorticoid commonly used in clinical practice,has lasting effects on offspring's learning and memory.Adult offspring rats of prenatal dexamethasone exposure(PDE)displayed significant impairments in novelty recognition and spatial learning memory,with some phenotypes maintained transgenerationally.PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations,and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory,but these changes failed to carry over to offspring of F5 and F7 generations.Mechanistically,altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission,which might be related to oocyte-specific high expression and transmission of miR-133a-3p.Together,PDE affects hippocampal excitatory synaptic transmission,with lasting consequences across generations,and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.

Amyloid-β depresses excitatory cholinergic synaptic transmission in Drosophila

Objective Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to cognitive dysfunctions like Alzheimer＇s disease （AD）. Although amyloid-β （Aβ） aggregation is a pathological hallmark of AD, the mechanisms by which Aβ peptides modulate cholinergic synaptic transmission and memory loss remain obscure. This study was aimed to investigate the potential synaptic modulation by Aβ of the cholinergic synapses between olfactory receptor neurons and projection neurons （PNs） in the olfactory lobe of the fruit fly. Methods Cholinergic spontaneous and miniature excitatory postsynaptic current （mEPSC） were recorded with whole-cell patch clamp from PNs in Drosophila AD models expressing Aβ40, Aβ42, or Aβ42Arc peptides in neural tissue. Results In fly pupae （2 days before eclosion）, overexpression of Aβ42 or Aβ42Arc, but not Aβ40, led to a significant decrease of mEPSC frequency, while overexpression of Aβ40, Aβ42, or Aβ42Arc had no significant effect on mEPSC amplitude. In contrast, Pavlovian olfactory associative learning and lifespan assays showed that both short-term memory and lifespan were decreased in the Drosophila models expressing Aβ40, Aβ42, or Aβ42Arc. Conclusion Both electrophysiological and behavioral results showed an effect of Aβ peptide on cholinergic synaptic transmission and suggest a possible mechanism by which Aβ peptides cause cholinergic neuron degeneration and the consequent memory loss.

Activities of nicotinic acetylcholine receptors modulate neurotransmission and synaptic architecture

The cholinergic system is involved in a broad spectrum of brain function, and its failure has been implicated in Alzheimer＇s disease. Acetylcholine transduces signals through muscarinic and nicotinic acetylcholine receptors, both of which influence synaptic plasticity and cognition. However, the mechanisms that relate the rapid gating of nicotinic acetylcholine receptors to persistent changes in brain function have remained elusive. Recent evidence indicates that nicotinic acetylcholine receptors activities affect synaptic morphology and density, which result in persistent rearrangements of neural connectivity. Further investigations of the relationships between nicotinic acetylcholine receptors and rearrangements of neural circuitry in the central nervous system may help understand the pathogenesis of Alzheimer＇s disease.

Resident immune responses to spinal cord injury:role of astrocytes and microglia

Spinal cord injury can be traumatic or non-traumatic in origin,with the latter rising in incidence and prevalence with the aging demographics of our society.Moreove r,as the global population ages,individuals with co-existent degenerative spinal pathology comprise a growing number of traumatic spinal cord injury cases,especially involving the cervical spinal cord.This makes recovery and treatment approaches particula rly challenging as age and comorbidities may limit regenerative capacity.For these reasons,it is critical to better understand the complex milieu of spinal cord injury lesion pathobiology and the ensuing inflammatory response.This review discusses microglia-specific purinergic and cytokine signaling pathways,as well as microglial modulation of synaptic stability and plasticity after injury.Further,we evaluate the role of astrocytes in neurotransmission and calcium signaling,as well as their border-forming response to neural lesions.Both the inflammatory and reparative roles of these cells have eluded our complete understanding and remain key therapeutic targets due to their extensive structural and functional roles in the nervous system.Recent advances have shed light on the roles of glia in neurotransmission and reparative injury responses that will change how interventions are directed.Understanding key processes and existing knowledge gaps will allow future research to effectively target these cells and harness their regenerative potential.

Inhibitory gamma-aminobutyric acidergic neurons in the anterior cingulate cortex participate in the comorbidity of pain and emotion

Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairments in inhibitory gamma-aminobutyric acid neurotransmission.This review primarily aims to outline the main circuitry(including the input and output connectivity)of the anterior cingulate cortex and classification and functions of different gamma-aminobutyric acidergic neurons;it also describes the neurotransmitters/neuromodulators affecting these neurons,their intercommunication with other neurons,and their importance in mental comorbidities associated with chronic pain disorders.Improving understanding on their role in pain-related mental comorbidities may facilitate the development of more effective treatments for these conditions.However,the mechanisms that regulate gamma-aminobutyric acidergic systems remain elusive.It is also unclear as to whether the mechanisms are presynaptic or postsynaptic.Further exploration of the complexities of this system may reveal new pathways for research and drug development.

Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage

The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is well-documented.Nevertheless,the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied.The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra.Our findings indicated that the reversible loss of field excitato ry postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids(L-alanine,glycine,L-glutamine,and L-serine)at their plasma concentrations.These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia,along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors.Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia.It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels,leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation.Thus,previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury.Understanding these pathways co uld highlight new therapeutic targets to mitigate brain injury.

Abnormal synaptic plasticity and impaired cognition in schizophrenia

Schizophrenia(SCZ)is a severe mental illness that affects several brain domains with relation to cognition and behaviour.SCZ symptoms are typically classified into three categories,namely,positive,negative,and cognitive.The etiology of SCZ is thought to be multifactorial and poorly understood.Accumulating evidence has indicated abnormal synaptic plasticity and cognitive impairments in SCZ.Synaptic plasticity is thought to be induced at appropriate synapses during memory formation and has a critical role in the cognitive symptoms of SCZ.Many factors,including synaptic structure changes,aberrant expression of plasticityrelated genes,and abnormal synaptic transmission,may influence synaptic plasticity and play vital roles in SCZ.In this article,we briefly summarize the morphology of the synapse,the neurobiology of synaptic plasticity,and the role of synaptic plasticity,and review potential mechanisms underlying abnormal synaptic plasticity in SCZ.These abnormalities involve dendritic spines,postsynaptic density,and long-term potentiation-like plasticity.We also focus on cognitive dysfunction,which reflects impaired connectivity in SCZ.Additionally,the potential targets for the treatment of SCZ are discussed in this article.Therefore,understanding abnormal synaptic plasticity and impaired cognition in SCZ has an essential role in drug therapy.

Genetic mechanisms underlying synaptic pathology in Autism Spectrum Disorder (ASD)

Autism spectrum disorder(ASD)is a neuronal developmental disorder that is characterized by de⁃fects both in social interaction and verbal communication,and is often accompanied by restricted interest,and repeti⁃tive and stereotyped behaviors.The prevalence of ASD is approximately 0.8%~1.2%in China.Although its etiology remains unclear in most cases,over 1000 genes or genomic loci have been linked to its pathogenic origin,indicating a strong genetic influence,as well as complicated pathogenic mechanisms.Here,we reviewed recent findings in the possible genetic effects on synaptic pathophysiology of ASD,and a particular focus was put on variants in genes that are related to synaptic morphology or functions,such as FMR1,NRXN,NLGN,SHANK and MeCP2.The synaptic pathology caused by these genetic defects may substantially contribute to the pathogenesis of ASD.This review out⁃lines several lines of evidence that have been recently reported to support the hypothesis that a genetic defect may lead to a synaptic pathology that may underlie the pathogenesis of ASD.

Expression and regulatory network of long noncoding RNA in rats after spinal cord hemisection injury

Long noncoding RNAs(lncRNAs)participate in a variety of biological processes and diseases.However,the expression and function of lncRNAs after spinal cord injury has not been extensively analyzed.In this study of right side hemisection of the spinal cord at T10,we detected the expression of lncRNAs in the proximal tissue of T10 lamina at different time points and found 445 lncRNAs and 6522 mRNA were differentially expressed.We divided the differentially expressed lncRNAs into 26 expression trends and analyzed Profile 25 and Profile 2,the two expression trends with the most significant difference.Our results showed that the expression of 68 lncRNAs in Profile 25 rose first and remained high 3 days post-injury.There were 387 mRNAs co-expressed with the 68 lncRNAs in Profile 25.The co-expression network showed that the co-expressed genes were mainly enriched in cell division,inflammatory response,FcγR-mediated cell phagocytosis signaling pathway,cell cycle and apoptosis.The expression of 56 lncRNAs in Profile2 first declined and remained low after 3 days post-injury.There were 387 mRNAs co-expressed with the 56 lncRNAs in Profile 2.The co-expression network showed that the co-expressed genes were mainly enriched in the chemical synaptic transmission process and in the signaling pathway of neuroactive ligand-receptor interaction.The results provided the expression and regulatory network of the main lncRNAs after spinal cord injury and clarified their co-expressed gene enriched biological processes and signaling pathways.These findings provide a new direction for the clinical treatment of spinal cord injury.

A cascade model of information processing and encoding for retinal prosthesis

Retinal prosthesis offers a potential treatment for individuals suffering from photoreceptor degeneration diseases.Establishing biological retinal models and simulating how the biological retina convert incoming light signal into spike trains that can be properly decoded by the brain is a key issue.Some retinal models have been presented,ranking from structural models inspired by the layered architecture to functional models originated from a set of specific physiological phenomena.However,Most of these focus on stimulus image compression,edge detection and reconstruction,but do not generate spike trains corresponding to visual image.In this study,based on stateof-the-art retinal physiological mechanism,including effective visual information extraction,static nonlinear rectification of biological systems and neurons Poisson coding,a cascade model of the retina including the out plexiform layer for information processing and the inner plexiform layer for information encoding was brought forward,which integrates both anatomic connections and functional computations of retina.Using MATLAB software,spike trains corresponding to stimulus image were numerically computed by four steps：linear spatiotemporal filtering,static nonlinear rectification,radial sampling and then Poisson spike generation.The simulated results suggested that such a cascade model could recreate visual information processing and encoding functionalities of the retina,which is helpful in developing artificial retina for the retinally blind.

Timp1 Deletion Induces Anxiety-like Behavior in Mice

The hippocampus is essential for learning and memory,but it also plays an important role in regulating emotional behavior,as hippocampal excitability and plasticity affect anxiety and fear.Brain synaptic plasticity may be regulated by tissue inhibitor of matrix metalloproteinase 1(TIMP1),a known protein inhibitor of extracellular matrix(ECM),and the expression of TIMP1 in the hippocampus can be induced by neuronal excitation and various stimuli.However,the involvement of Timp1 in fear learning,anxiety,and hippocampal synaptic function remains to be established.Our study of Timp1 function in vivo revealed that Timp1 knockout mice exhibit anxiety-like behavior but normal fear learning.Electrophysiological results suggested that Timp1 knockout mice showed hyperactivity in the ventral CA1 region,but the basic synaptic transmission and plasticity were normal in the Schaffer collateral pathway.Taken together,our results suggest that deletion of Timp1 in vivo leads to the occurrence of anxiety behaviors,but that Timp1 is not crucial for fear learning.

CCL2/CCR2 Contributes to the Altered Excitatory-inhibitory Synaptic Balance in the Nucleus Accumbens Shell Following Peripheral Nerve Injury-induced Neuropathic Pain

The medium spiny neurons(MSNs)in the nucleus accumbens(NAc)integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output.Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation(SNL).SNL increased the frequency,but not the amplitude of spontaneous inhibitory postsynaptic currents(sIPSCs),and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents(sEPSCs)in the MSNs.SNL also decreased the paired-pulse ratio(PPR)of evoked IPSCs but increased the PPR of evoked EPSCs.Moreover,acute bath application of C–C motif chemokine ligand 2(CCL2)increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs,and especially strengthened the amplitude of N-methyl-D-aspartate receptor(NMDAR)-mediated miniature EPSCs.Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio.Finally,Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression(LTD)in the NAc after SNL.These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.

Glutamatergic CYLD deletion leads to aberrant excitatory activity in the basolateral amygdala:association with enhanced cued fear expression

Neuronal activity,synaptic transmission,and molecular changes in the basolateral amygdala play critical roles in fear memory.Cylindromatosis(CYLD)is a deubiquitinase that negatively regulates the nuclear factor kappa-B pathway.CYLD is well studied in non-neuronal cells,yet underinvestigated in the brain,where it is highly expressed.Emerging studies have shown involvement of CYLD in the remodeling of glutamatergic synapses,neuroinflammation,fear memory,and anxiety-and autism-like behaviors.However,the precise role of CYLD in glutamatergic neurons is largely unknown.Here,we first proposed involvement of CYLD in cued fear expression.We next constructed transgenic model mice with specific deletion of Cyld from glutamatergic neurons.Our results show that glutamatergic CYLD deficiency exaggerated the expression of cued fear in only male mice.Further,loss of CYLD in glutamatergic neurons resulted in enhanced neuronal activation,impaired excitatory synaptic transmission,and altered levels of glutamate receptors accompanied by over-activation of microglia in the basolateral amygdala of male mice.Altogether,our study suggests a critical role of glutamatergic CYLD in maintaining normal neuronal,synaptic,and microglial activation.This may contribute,at least in part,to cued fear expression.

Lack of interferon regulatory factor 3 leads to anxiety/depression-like behaviors through disrupting the balance of neuronal excitation and inhibition in mice

Disrupting the balance of neuronal excitation and inhibition (E/I) is an important pathogenic mechanism of anxiety and depression. Interferon regulatory factor 3 (IRF3) plays a key role in the innate immune response, and activation of IRF3 triggers the expression of type I interferons and downstream interferon-stimulated genes, which are associated with anxiety and depression. However, whether IRF3 participates in the pathogenesis of anxiety/depression by regulating E/I balance remains poorly understood. Here, we reported that global knockout (KO) of IRF3 (IRF3^(−/−)) significantly increased anxiety/depression-like behaviors, but did not affect normal spatial learning and memory. Compared with wild type (WT) control mice, the E/I balance was disrupted, as reflected by enhanced glutamatergic transmission and decreased GABAergic transmission in the neurons of hippocampal CA1 and medial prefrontal cortex (mPFC) in IRF3-KO mice. Importantly, genetic rescue of IRF3 expression by adeno-associated virus (AAV) was sufficient to alleviate anxiety/depression-like behaviors and restore the neuronal E/I balance in IRF3-KO mice. Taken together, our results indicate that IRF3 is critical in maintaining neuronal E/I balance, thereby playing an essential role in ensuring emotional stability.

Deficiency of anti-inflammatory cytokine IL-4 leads to neural hyperexcitability and aggravates cerebral ischemia-reperfusion injury

Systematic administration of anti-inflammatory cytokine interleukin 4(IL-4)has been shown to improve recovery after cerebral ischemic stroke.However,whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown.Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia-repertusion(I/R)injury.In multi-electrode array(MEA)recordings,IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons.IL-4 mRNA and protein expressions are upregulated after I/R injury.Genetic deletion of 11-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation(OGD)injury in cortical neurons.Conversely,supplemental IL-4 protects 11-4-/-cortical neurons against OGD injury.Mechanistically,cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4-/-mice.Furthermore,upregulation of Nav1.1 channel,and downregulations of KCa3.1 channel and a6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4-/-mice.Taken together,our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury,thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.

Drosophila Studies on Autism Spectrum Disorders

In the past decade, numerous genes associated with autism spectrum disorders（ASDs） have been identified. These genes encode key regulators of synaptogenesis,synaptic function, and synaptic plasticity. Drosophila is a prominent model system for ASD studies to define novel genes linked to ASDs and decipher their molecular roles in synaptogenesis, synaptic function, synaptic plasticity, and neural circuit assembly and consolidation. Here, we review Drosophila studies on ASD genes that regulate synaptogenesis, synaptic function, and synaptic plasticity through modulating chromatin remodeling, transcription, protein synthesis and degradation, cytoskeleton dynamics, and synaptic scaffolding.