Intrinsic Neuronal Excitability Research Articles

Single cocaine exposure attenuates the intrinsic excitability of CRH neurons in the ventral BNST via Sigma-1 receptors.

The ventral bed nucleus of the stria terminalis (vBNST) plays a key role in cocaine addiction, especially relapse. However, the direct effects of cocaine on corticotropin-releasing hormone (CRH) neurons in the vBNST remain unclear. Here, we identify that cocaine exposure can remarkably attenuate the intrinsic excitability of CRH neurons in the vBNST in vitro. Accumulating studies reveal the crucial role of Sigma-1 receptors (Sig-1Rs) in modulating cocaine addiction. However, to the authors' best knowledge no investigations have explored the role of Sig-1Rs in the vBNST, let alone CRH neurons. Given that cocaine acts as a type of Sig-1Rs agonist, and the dramatic role of Sig-1Rs played in intrinsic excitability of neurons as well as cocaine addiction, we employ BD1063 a canonical Sig-1Rs antagonist to block the effects of cocaine, and significantly recover the excitability of CRH neurons. Together, we suggest that cocaine exposure leads to the firing rate depression of CRH neurons in the vBNST via binding to Sig-1Rs.

Inhibition of 14-3-3 proteins increases the intrinsic excitability of mouse hippocampal CA1 pyramidal neurons.

14-3-3 proteins are a family of regulatory proteins that are abundantly expressed in the brain and enriched at the synapse. Dysfunctions of these proteins have been linked to neurodevelopmental and neuropsychiatric disorders. Our group has previously shown that functional inhibition of these proteins by a peptide inhibitor, difopein, in the mouse brain causes behavioural alterations and synaptic plasticity impairment in the hippocampus. Recently, we found an increased cFOS expression in difopein-expressing dorsal CA1 pyramidal neurons, indicating enhanced neuronal activity by 14-3-3 inhibition in these cells. In this study, we used slice electrophysiology to determine the effects of 14-3-3 inhibition on the intrinsic excitability of CA1 pyramidal neurons from a transgenic 14-3-3 functional knockout (FKO) mouse line. Our data demonstrate an increase in intrinsic excitability associated with 14-3-3 inhibition, as well as reveal action potential firing pattern shifts after novelty-induced hyperlocomotion in the 14-3-3 FKO mice. These results provide novel information on the role 14-3-3 proteins play in regulating intrinsic and activity-dependent neuronal excitability in the hippocampus.

The homeostatic effects of the RE-1 silencing transcription factor on cortical networks are altered under ictogenic conditions in the mouse.

The Repressor Element-1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental stages, REST downregulation promotes neuronal differentiation and the acquisition of the neuronal phenotype. In addition, postnatal fluctuations in REST expression contribute to shaping neuronal networks and maintaining network homeostasis. Here we investigate the role of the early postnatal deletion of neuronal REST in the assembly and strength of excitatory and inhibitory synaptic connections. We investigated excitatory and inhibitory synaptic transmission by patch-clamp recordings in acute neocortical slices in a conditional knockout mouse model (RestGTi) in which Rest was deleted by delivering PHP.eB adeno-associated viruses encoding CRE recombinase under the control of the human synapsin I promoter in the lateral ventricles of P0-P1 pups. We show that, under physiological conditions, Rest deletion increased the intrinsic excitability of principal cortical neurons in the primary visual cortex and the density and strength of excitatory synaptic connections impinging on them, without affecting inhibitory transmission. Conversely, in the presence of a pathological excitation/inhibition imbalance induced by pentylenetetrazol, Rest deletion prevented the increase in synaptic excitation and decreased seizure severity. The data indicate that REST exerts distinct effects on the excitability of cortical circuits depending on whether it acts under physiological conditions or in the presence of pathologic network hyperexcitability. In the former case, REST preserves a correct excitatory/inhibitory balance in cortical circuits, while in the latter REST loses its homeostatic activity and may become pro-epileptogenic.

GADD45B in the ventral hippocampal CA1 modulates aversive memory acquisition and spatial cognition

AimsThis study was designed to investigate the role of growth arrest and DNA damage-inducible β (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. Main methodsAdeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. Key findingsKnockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SignificanceThese results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.

The Role of Cerebellar Intrinsic Neuronal Excitability, Synaptic Plasticity, and Perineuronal Nets in Eyeblink Conditioning.

Evidence is strong that, in addition to fine motor control, there is an important role for the cerebellum in cognition and emotion. The deep nuclei of the mammalian cerebellum also contain the highest density of perineural nets-mesh-like structures that surround neurons-in the brain, and it appears there may be a connection between these nets and cognitive processes, particularly learning and memory. Here, we review how the cerebellum is involved in eyeblink conditioning-a particularly well-understood form of learning and memory-and focus on the role of perineuronal nets in intrinsic membrane excitability and synaptic plasticity that underlie eyeblink conditioning. We explore the development and role of perineuronal nets and the in vivo and in vitro evidence that manipulations of the perineuronal net in the deep cerebellar nuclei affect eyeblink conditioning. Together, these findings provide evidence of an important role for perineuronal net in learning and memory.

LncRNA Anxa10-203 enhances Mc1r mRNA stability to promote neuropathic pain by recruiting DHX30 in the trigeminal ganglion

BackgroundTrigeminal nerve injury is one of the most serious complications in oral clinics, and the subsequent chronic orofacial pain is a consumptive disease. Increasing evidence demonstrates long non-coding RNAs (lncRNAs) play an important role in the pathological process of neuropathic pain. This study aims to explore the function and mechanism of LncRNA Anxa10-203 in the development of orofacial neuropathic pain.MethodsA mouse model of orofacial neuropathic pain was established by chronic constriction injury of the infraorbital nerve (CCI-ION). The Von Frey test was applied to evaluate hypersensitivity of mice. RT-qPCR and/or Western Blot were performed to analyze the expression of Anxa10-203, DHX30, and MC1R. Cellular localization of target genes was verified by immunofluorescence and RNA fluorescence in situ hybridization. RNA pull-down and RNA immunoprecipitation were used to detect the interaction between the target molecules. Electrophysiology was employed to assess the intrinsic excitability of TG neurons (TGNs) in vitro.ResultsAnxa10-203 was upregulated in the TG of CCI-ION mice, and knockdown of Anxa10-203 relieved neuropathic pain. Structurally, Anxa10-203 was located in the cytoplasm of TGNs. Mechanistically, Mc1r expression was positively correlated with Anxa10-203 and was identified as the functional target of Anxa10-203. Besides, Anxa10-203 recruited RNA binding protein DHX30 and formed the Anxa10-203/DHX30 complex to enhance the stability of Mc1r mRNA, resulting in the upregulation of MC1R, which contributed to the enhancement of the intrinsic activity of TGNs in vitro and orofacial neuropathic pain in vivo.ConclusionsLncRNA Anxa10-203 in the TG played an important role in orofacial neuropathic pain and mediated mechanical allodynia in CCI-ION mice by binding with DHX30 to upregulate MC1R expression.Graphical The up-regulated lncRNA Anxa10-203 in the trigeminal ganglion of CCI-ION mice interacts with DHX30 to contribute to the excitability of TG neurons and orofacial pain by enhancing Mc1r mRNA stability.

Transplantation of dorsal root ganglia overexpressing the NaChBac sodium channel improves locomotion after complete SCI

Spinal cord injury (SCI) is a debilitating condition currently lacking treatment. Severe SCI causes the loss of most supraspinal inputs and neuronal activity caudal to the injury, which, coupled with the limited endogenous capacity for spontaneous regeneration, can lead to complete functional loss even in anatomically incomplete lesions. We hypothesized that transplantation of mature dorsal root ganglia (DRG), genetically modified to express the NaChBac sodium channel, could serve as a therapeutic option for functionally complete SCI. We found that NaChBac expression increased the intrinsic excitability of DRG neurons, promoted cell survival and neurotrophic factor secretion in vitro. Transplantation of NaChBac-expressing dissociated DRGs improved voluntary locomotion seven weeks after injury compared to control groups. Animals transplanted with NaChBac-expressing DRGs also possessed higher tubulin-positive neuronal fiber and myelin preservation, although serotonergic descending fibers remained unaffected. We observed early preservation of the corticospinal tract fourteen days after injury and transplantation which was lost seven weeks after injury. Nevertheless, transplantation of NaChBac-expressing DRGs increased the neuronal excitatory input, by increased number of VGlut2 contacts, immediately caudal to the injuries. Our work suggests that the transplantation of NaChBac-expressing dissociated DRGs can rescue significant motor function retaining an excitatory neuronal relay activity immediately caudal to injury.

Keeping Your Brain in Balance: Homeostatic Regulation of Network Function.

To perform computations with the efficiency necessary for animal survival, neocortical microcircuits must be capable of reconfiguring in response to experience, while carefully regulating excitatory and inhibitory connectivity to maintain stable function. This dynamic fine-tuning is accomplished through a rich array of cellular homeostatic plasticity mechanisms that stabilize important cellular and network features such as firing rates, information flow, and sensory tuning properties. Further, these functional network properties can be stabilized by different forms of homeostatic plasticity, including mechanisms that target excitatory or inhibitory synapses, or that regulate intrinsic neuronal excitability. Here we discuss which aspects of neocortical circuit function are under homeostatic control, how this homeostasis is realized on the cellular and molecular levels, and the pathological consequences when circuit homeostasis is impaired. A remaining challenge is to elucidate how these diverse homeostatic mechanisms cooperate within complex circuits to enable them to be both flexible and stable. Expected final online publication date for the Annual Review of Neuroscience, Volume 47 is July 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Static magnetic stimulation induces structural plasticity at the axon initial segment of inhibitory cortical neurons

Static magnetic stimulation (SMS) is a form of non-invasive brain stimulation that alters neural activity and induces neural plasticity that outlasts the period of stimulation. This can modify corticospinal excitability or motor behaviours, suggesting that SMS may alter the intrinsic excitability of neurons. In mammalian neurons, the axon initial segment (AIS) is the site of action potential initiation and undergoes structural plasticity (changes in length and position from the soma) as a homeostatic mechanism to counteract chronic changes in neuronal activity. We investigated whether the chronic application of SMS (6 and 48 h, 0.5 T) induces structural AIS plasticity in postnatally derived primary cortical neurons. Following 6 h of SMS, we observed a shortening in mean AIS length compared to control, that persisted 24 h post stimulation. In contrast, 48 h of SMS induced an immediate distal shift that persisted 24 h post-stimulation. Pharmacological blockade of voltage gated L/T-type calcium channels during stimulation did not prevent SMS-induced AIS structural plasticity. Our findings provide the foundation to expand the use of chronic SMS as a non-invasive method to promote AIS plasticity.

Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions.

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

Reversing Aging: Decline in Complex Olfactory Learning Can be Rectified by Restoring Intrinsic Plasticity of Hippocampal CA1 Pyramidal Neurons.

The acquisition of complex rules requires modifications in intrinsic plasticity of excitatory neurons within relevant brain areas. Olfactory discrimination (OD) rule learning occludes slow calcium-dependent potassium current (sIAHP ) in piriform cortex (PC) pyramidal neurons, which increases their intrinsic neuronal excitability. Similar learning-induced sIAHP changes are demonstrated in hippocampal CA1. The shutdown of sIAHP is mediated by the metabotropic activation of the kainate subtype glutamatergic receptor, GluK2. Here, the duration of training required for OD rule learning increased significantly as the mice matured and aged is first shown, which appears earlier in 5xFAD mice. At the cellular biophysical level, aging is accompanied by reduction in the post-burst AHP in these neurons, while neuronal excitability remains stable. This is in contrast to aging CA1 neurons that exhibit enhanced post-burst AHPs in previous reports. Kainate reduces post-burst AHP in adults, but not in aged PC neurons, whereas it reduces post-burst AHPs in hippocampal CA1 pyramidal neurons of both young and aged mice. Overexpression of GluK2 in CA1 neurons restores OD learning capabilities in aged wild-type and 5xFAD mice, to a level comparable to young adults. Activation of GluK2 receptors in selectively vulnerable neurons can prevent aging-related cognitive decline is suggested.

Altered synaptic plasticity at hippocampal CA1-CA3 synapses in Alzheimer's disease: integration of amyloid precursor protein intracellular domain and amyloid beta effects into computational models.

Alzheimer's disease (AD) is a progressive memory loss and cognitive dysfunction brain disorder brought on by the dysfunctional amyloid precursor protein (APP) processing and clearance of APP peptides. Increased APP levels lead to the production of AD-related peptides including the amyloid APP intracellular domain (AICD) and amyloid beta (Aβ), and consequently modify the intrinsic excitability of the hippocampal CA1 pyramidal neurons, synaptic protein activity, and impair synaptic plasticity at hippocampal CA1-CA3 synapses. The goal of the present study is to build computational models that incorporate the effect of AD-related peptides on CA1 pyramidal neuron and hippocampal synaptic plasticity under the AD conditions and investigate the potential pharmacological treatments that could normalize hippocampal synaptic plasticity and learning in AD. We employ a phenomenological N-methyl-D-aspartate (NMDA) receptor-based voltage-dependent synaptic plasticity model that includes the separate receptor contributions on long-term potentiation (LTP) and long-term depression (LTD) and embed it into the a detailed compartmental model of CA1 pyramidal neuron. Modeling results show that partial blockade of Glu2NB-NMDAR-gated channel restores intrinsic excitability of a CA1 pyramidal neuron and rescues LTP in AICD and Aβ conditions. The model provides insight into the complex interactions in AD pathophysiology and suggests the conditions under which the synchronous activation of a cluster of synaptic inputs targeting the dendritic tree of CA1 pyramidal neuron leads to restored synaptic plasticity.

Elevated Heme Drives Evoked and Ongoing Pain Behaviors in WT Mice By Sensitization of Dorsal Root Ganglia Neurons

Individuals with sickle cell disease (SCD) suffer from complex stimulus-evoked and ongoing pain that is mediated in part by the hyperexcitability of their peripheral sensory neurons. However, it is unclear whether acute or chronic elevation of cell free heme, a key pathological feature of SCD, contributes to the aberrant activity of sensory neurons. Thus, determining whether heme drives pain behavior and enhanced excitability of dorsal root ganglia (DRG) primary sensory neurons involved in pain signal transduction is critical for the development of targeted pain therapies for SCD. In the current experiments, we use evoked and ongoing pain behavior assays and in vitro calcium imaging to evaluate the hypothesis that acute increases in heme causes direct sensitization of nociceptive DRG neurons in wildtype (WT) mice. Our preliminary data reveal that similar to pain behaviors in the mouse model of SCD, hind paw injection of heme into WT mice induces mechanical hypersensitivity (Figure 1). We also observed increased aversive responses to dynamic paintbrush and noxious needle stimulation as well as the onset of paw licking behavior suggesting that heme also drives ongoing, non-evoked pain. These data suggest that axon terminals in the skin become rapidly sensitized when exposed to elevated heme. We next administered heme to primary cultured DRG neurons in vitro and observed calcium flux across the neuronal cell membrane that was dependent on extracellular calcium. To determine if heme directly triggers action potentials or enhances spontaneous activity of sensory neurons, we conducted electrophysiological recordings of neuronal activity in neurons held at resting membrane potential at physiological temperature. Our preliminary data indicate that exposure to heme may directly enhance neuronal action potential firing frequency (Figure 2). Together, these data suggest that heme opens calcium channels on sensory neurons to initiate pain signal transduction and drive acute pain behaviors. We plan to conduct additional non-evoked pain behavior assays including facial grimace analysis and conditioned place aversion to determine whether heme injection is sufficient to drive ongoing pain. We will further determine whether exposure to heme enhances the intrinsic excitability of mechanical and cold sensitive neurons as heme-dependent hyperactivity of these neurons may lead to our observed acute onset mechanical and cold hypersensitivity in heme-injected mice. Completion of these experiments will shed light on the contributions of cell free heme to SCD pain and illuminate downstream effectors that may be targeted to provide analgesic relief for this historically understudied and debilitating disease.

Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons

Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of invitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.

Low-Frequency Stimulation of Trpv1-Lineage Peripheral Afferents Potentiates the Excitability of Spino-Periaqueductal Gray Projection Neurons.

High-threshold dorsal root ganglion (HT DRG) neurons fire at low frequencies during inflammatory injury, and low-frequency stimulation (LFS) of HT DRG neurons selectively potentiates excitatory synapses onto spinal neurons projecting to the periaqueductal gray (spino-PAG). Here, in male and female mice, we have identified an underlying peripheral sensory population driving this plasticity and its effects on the output of spino-PAG neurons. We provide the first evidence that Trpv1-lineage sensory neurons predominantly induce burst firing, a unique mode of neuronal activity, in lamina I spino-PAG projection neurons. We modeled inflammatory injury by optogenetically stimulating Trpv1+ primary afferents at 2 Hz for 2 min (LFS), as peripheral inflammation induces 1-2 Hz firing in high-threshold C fibers. LFS of Trpv1+ afferents enhanced the synaptically evoked and intrinsic excitability of spino-PAG projection neurons, eliciting a stable increase in the number of action potentials (APs) within a Trpv1+ fiber-induced burst, while decreasing the intrinsic AP threshold and increasing the membrane resistance. Further experiments revealed that this plasticity required Trpv1+ afferent input, postsynaptic G protein-coupled signaling, and NMDA receptor activation. Intriguingly, an inflammatory injury and heat exposure in vivo also increased APs per burst, in vitro These results suggest that inflammatory injury-mediated plasticity is driven though Trpv1+ DRG neurons and amplifies the spino-PAG pathway. Spinal inputs to the PAG could play an integral role in its modulation of heat sensation during peripheral inflammation, warranting further exploration of the organization and function of these neural pathways.

Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling.

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

Smith–Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith–Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

Characterization of Na+ currents regulating intrinsic excitability of optic tectal neurons.

Developing neurons adapt their intrinsic excitability to maintain stable output despite changing synaptic input. The mechanisms behind this process remain unclear. In this study, we examined Xenopus optic tectal neurons and found that the expressions of Nav1.1 and Nav1.6 voltage-gated Na+ channels are regulated during changes in intrinsic excitability, both during development and becsuse of changes in visual experience. Using whole-cell electrophysiology, we demonstrate the existence of distinct, fast, persistent, and resurgent Na+ currents in the tectum, and show that these Na+ currents are co-regulated with changes in Nav channel expression. Using antisense RNA to suppress the expression of specific Nav subunits, we found that up-regulation of Nav1.6 expression, but not Nav1.1, was necessary for experience-dependent increases in Na+ currents and intrinsic excitability. Furthermore, this regulation was also necessary for normal development of sensory guided behaviors. These data suggest that the regulation of Na+ currents through the modulation of Nav1.6 expression, and to a lesser extent Nav1.1, plays a crucial role in controlling the intrinsic excitability of tectal neurons and guiding normal development of the tectal circuitry.

Deactivation of dorsal CA1 pyramidal neurons projecting to medial prefrontal cortex contributes to neuropathic pain and short-term memory impairment.

Neuropathic pain after peripheral nerve injury is a multidimensional experience that includes sensory, affective, and cognitive components that interact with one another. Hypoexcitation of the medial prefrontal cortex (mPFC) was observed in mice with peripheral nerve injury, but the changes in neural inputs onto the mPFC have not been completely explored. Here, we report that the neural terminals from the dorsal hippocampus CA1 (dCA1) form excitatory connection with layer 5 pyramidal neurons in the prelimbic area (PrL) of the mPFC. Spared nerve injury (SNI) induced a reduction in the intrinsic excitability of dCA1 pyramidal neurons innervating the PrL and impairment in excitatory synaptic transmission onto dCA1 pyramidal cells. Specifically, activating the neural circuit from dCA1 to mPFC alleviated neuropathic pain behaviors and improved novel object recognition ability in SNI mice, whereas deactivating this pathway in naïve animals recapitulated tactile allodynia and memory deficits. These results indicated that hypoactivity in dCA1 pyramidal cells after SNI in turn deactivated layer 5 pyramidal neurons in PrL and ultimately caused pain hypersensitivity and memory deficits.

MiR-218 Promotes Dopaminergic Differentiation and Controls Neuron Excitability and Neurotransmitter Release through the Regulation of a Synaptic-Related Genes Network.

In the brain, microRNAs (miRNAs) are believed to play a role in orchestrating synaptic plasticity at a higher level by acting as an additional mechanism of translational regulation, alongside the mRNA/polysome system. Despite extensive research, our understanding of the specific contribution of individual miRNA to the function of dopaminergic neurons (DAn) remains limited. By performing a dopaminergic-specific miRNA screening, we have identified miR-218 as a critical regulator of DAn activity in male and female mice. We have found that miR-218 is specifically expressed in mesencephalic DAn and is able to promote dopaminergic differentiation of embryonic stem cells and functional maturation of transdifferentiated induced DA neurons. Midbrain-specific deletion of both genes encoding for miR-218 (referred to as miR-218-1 and mir218-2) affects the expression of a cluster of synaptic-related mRNAs and alters the intrinsic excitability of DAn, as it increases instantaneous frequencies of evoked action potentials, reduces rheobase current, affects the ionic current underlying the action potential after hyperpolarization phase, and reduces dopamine efflux in response to a single electrical stimulus. Our findings provide a comprehensive understanding of the involvement of miR-218 in the dopaminergic system and highlight its role as a modulator of dopaminergic transmission.SIGNIFICANCE STATEMENT In the past decade, several miRNAs have emerged as potential regulators of synapse activity through the modulation of specific gene expression. Among these, we have identified a dopaminergic-specific miRNA, miR-218, which is able to promote dopaminergic differentiation and regulates the translation of an entire cluster of synapse related mRNAs. Deletion of miR-218 has notable effects on dopamine release and alters the intrinsic excitability of dopaminergic neurons, indicating a direct control of dopaminergic activity by miR-218.