Hyperpolarization-Activated Current (Ih) Is Reduced in Hippocampal Neurons from Gabra5?/? Mice

Changes in the expression of γ-aminobutyric acid type A (GABA_A) receptors can either drive or mediate homeostatic alterations in neuronal excitability. A homeostatic relationship between α5 subunit-containing GABA_A (α5GABA_A) receptors that generate a tonic inhibitory conductance, and HCN channels that generate a hyperpolarization-activated cation current (I_h) was recently described for cortical neurons, where a reduction in I_h was accompanied by a reciprocal increase in the expression of α5GABA_A receptors resulting in the preservation of dendritosomatic synaptic function. Here, we report that in mice that lack the α5 subunit gene (Gabra5−/−), cultured embryonic hippocampal pyramidal neurons and ex vivo CA1 hippocampal neurons unexpectedly exhibited a decrease in I_h current density (by 40% and 28%, respectively), compared with neurons from wild-type (WT) mice. The resting membrane potential and membrane hyperpolarization induced by blockade of I_h with ZD-7288 were similar in cultured WT and Gabra5−/− neurons. In contrast, membrane hyperpolarization measured after a train of action potentials was lower in Gabra5−/− neurons than in WT neurons. Also, membrane impedance measured in response to low frequency stimulation was greater in cultured Gabra5−/− neurons. Finally, the expression of HCN1 protein that generates I_h was reduced by 41% in the hippocampus of Gabra5−/− mice. These data indicate that loss of a tonic GABAergic inhibitory conductance was followed by a compensatory reduction in I_h. The results further suggest that the maintenance of resting membrane potential is preferentially maintained in mature and immature hippocampal neurons through the homeostatic co-regulation of structurally and biophysically distinct cation and anion channels.     

Modeling Hermissenda: II. Effects of variations in type-B cell excitability, synaptic strength, and network architecture

Because the Hermissenda eye is relatively simple and its cells well characterized, it provides an attractive preparation for detailed computational analysis. To examine the neural mechanisms of learning in this system, we developed multicompartmental models of the type-A and type-B photoreceptors, simulated the eye, and asked three questions: First, how do conductance changes affect cells in a network as compared with those in isolation; second, what are the relative contributions of increases in B-cell excitability and synaptic strength to network output; and third, how do these contributions vary as a function of network architecture? We found that reductions in the type-B cells of two K⁺ currents, I _A and I _C, differentially affected the type-B cells themselves, with I _C reductions increasing firing rate (excitability) in response to light, and I _A reductions increasing quantal output (synaptic strength) onto postsynaptic targets. Increases in either type-B cell excitability or synaptic strength, induced directly or indirectly, each suppressed A-cell photoresponses, and the combined effect of both changes occurring together was greater than either alone. To examine the effects of network architecture, we compared the full network with a simple feedforward B-A pair and intermediate configurations. Compared with a feedforward pair, the complete network exhibited greater A-cell sensitivity to B-cell changes. This was due to many factors, including an increased number of B-cells (which increased B-cell impact on A-cells), A-B feedback inhibition (which slowed both cell types and altered spike timing relationships), and B-B lateral inhibition (which reduced B-cell sensitivity to intrinsic biophysical modifications). These results suggest that an emergent property of the network is an increase both in the rate of information acquisition (“learning”) and in the amount of information that can be stored (“memory”).     

Shal/K(v)4 channels are required for maintaining excitability during repetitive firing and normal locomotion in Drosophila

Background

Rhythmic behaviors, such as walking and breathing, involve the coordinated activity of central pattern generators in the CNS, sensory feedback from the PNS, to motoneuron output to muscles. Unraveling the intrinsic electrical properties of these cellular components is essential to understanding this coordinated activity. Here, we examine the significance of the transient A-type K⁺ current (I_A), encoded by the highly conserved Shal/K_v4 gene, in neuronal firing patterns and repetitive behaviors. While I_A is present in nearly all neurons across species, elimination of I_A has been complicated in mammals because of multiple genes underlying I_A, and/or electrical remodeling that occurs in response to affecting one gene.

Methodology/Principal Findings

In Drosophila, the single Shal/K_v4 gene encodes the predominant I_A current in many neuronal cell bodies. Using a transgenically expressed dominant-negative subunit (DNK_v4), we show that I_A is completely eliminated from cell bodies, with no effect on other currents. Most notably, DNK_v4 neurons display multiple defects during prolonged stimuli. DNK_v4 neurons display shortened latency to firing, a lower threshold for repetitive firing, and a progressive decrement in AP amplitude to an adapted state. We record from identified motoneurons and show that Shal/K_v4 channels are similarly required for maintaining excitability during repetitive firing. We then examine larval crawling, and adult climbing and grooming, all behaviors that rely on repetitive firing. We show that all are defective in the absence of Shal/K_v4 function. Further, knock-out of Shal/K_v4 function specifically in motoneurons significantly affects the locomotion behaviors tested.

Conclusions/Significance

Based on our results, Shal/K_v4 channels regulate the initiation of firing, enable neurons to continuously fire throughout a prolonged stimulus, and also influence firing frequency. This study shows that Shal/K_v4 channels play a key role in repetitively firing neurons during prolonged input/output, and suggests that their function and regulation are important for rhythmic behaviors.     

Conventional measures of intrinsic excitability are poor estimators of neuronal activity under realistic synaptic inputs

Activity-dependent regulation of intrinsic excitability has been shown to greatly contribute to the overall plasticity of neuronal circuits. Such neuroadaptations are commonly investigated in patch clamp experiments using current step stimulation and the resulting input-output functions are analyzed to quantify alterations in intrinsic excitability. However, it is rarely addressed, how such changes translate to the function of neurons when they operate under natural synaptic inputs. Still, it is reasonable to expect that a strong correlation and near proportional relationship exist between static firing responses and those evoked by synaptic drive. We challenge this view by performing a high-yield electrophysiological analysis of cultured mouse hippocampal neurons using both standard protocols and simulated synaptic inputs via dynamic clamp. We find that under these conditions the neurons exhibit vastly different firing responses with surprisingly weak correlation between static and dynamic firing intensities. These contrasting responses are regulated by two intrinsic K-currents mediated by Kv1 and K_ir channels, respectively. Pharmacological manipulation of the K-currents produces differential regulation of the firing output of neurons. Static firing responses are greatly increased in stuttering type neurons under blocking their Kv1 channels, while the synaptic responses of the same neurons are less affected. Pharmacological blocking of K_ir-channels in delayed firing type neurons, on the other hand, exhibit the opposite effects. Our subsequent computational model simulations confirm the findings in the electrophysiological experiments and also show that adaptive changes in the kinetic properties of such currents can even produce paradoxical regulation of the firing output.     

Targeted Deletion of Kcne2 Impairs HCN Channel Function in Mouse Thalamocortical Circuits

Background

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate the pacemaking current, I_h, which regulates neuronal excitability, burst firing activity, rhythmogenesis, and synaptic integration. The physiological consequence of HCN activation depends on regulation of channel gating by endogenous modulators and stabilization of the channel complex formed by principal and ancillary subunits. KCNE2 is a voltage-gated potassium channel ancillary subunit that also regulates heterologously expressed HCN channels; whether KCNE2 regulates neuronal HCN channel function is unknown.

Methodology/Principal Findings

We investigated the effects of Kcne2 gene deletion on I_h properties and excitability in ventrobasal (VB) and cortical layer 6 pyramidal neurons using brain slices prepared from Kcne2 ^+/+ and Kcne2 ^−/− mice. Kcne2 deletion shifted the voltage-dependence of I_h activation to more hyperpolarized potentials, slowed gating kinetics, and decreased I_h density. Kcne2 deletion was associated with a reduction in whole-brain expression of both HCN1 and HCN2 (but not HCN4), although co-immunoprecipitation from whole-brain lysates failed to detect interaction of KCNE2 with HCN1 or 2. Kcne2 deletion also increased input resistance and temporal summation of subthreshold voltage responses; this increased intrinsic excitability enhanced burst firing in response to 4-aminopyridine. Burst duration increased in corticothalamic, but not thalamocortical, neurons, suggesting enhanced cortical excitatory input to the thalamus; such augmented excitability did not result from changes in glutamate release machinery since miniature EPSC frequency was unaltered in Kcne2 ^−/− neurons.

Conclusions/Significance

Loss of KCNE2 leads to downregulation of HCN channel function associated with increased excitability in neurons in the cortico-thalamo-cortical loop. Such findings further our understanding of the normal physiology of brain circuitry critically involved in cognition and have implications for our understanding of various disorders of consciousness.     

Cholinergic modulation of synaptic integration and dendritic excitability in the striatum

Modulatory interneurons such as, the cholinergic interneuron, are always a perplexing subject to study. Far from clear-cut distinctions such as excitatory or inhibitory, modulating interneurons can have many, often contradictory effects. The striatum is one of the most densely expressing brain areas for cholinergic markers, and actylcholine (ACh) plays an important role in regulating synaptic transmission and cellular excitability. Every cell type in the striatum has receptors for ACh. Yet even for a given cell type, ACh affecting different receptors can have seemingly opposing roles. This review highlights relevant effects of ACh on medium spiny neurons (MSNs) of the striatum and suggests how its many effects may work in concert to modulate MSN firing properties.     

Restoration of Glutamatergic Transmission by Dopamine D4 Receptors in Stressed Animals

The prefrontal cortex (PFC), a key brain region for cognitive and emotional processes, is highly regulated by dopaminergic inputs. The dopamine D₄ receptor, which is enriched in PFC, has been implicated in mental disorders, such as attention deficit-hyperactivity disorder and schizophrenia. Recently we have found homeostatic regulation of AMPA receptor-mediated synaptic transmission in PFC pyramidal neurons by the D₄ receptor, providing a potential mechanism for D₄ in stabilizing cortical excitability. Because stress is tightly linked to adaptive and maladaptive changes associated with mental health and disorders, we examined the synaptic actions of D₄ in stressed rats. We found that neural excitability was elevated by acute stress and dampened by repeated stress. D₄ activation produced a potent reduction of excitatory transmission in acutely stressed animals and a marked increase of excitatory transmission in repeatedly stressed animals. These effects of D₄ targeted GluA2-lacking AMPA receptors and relied on the bi-directional regulation of calcium/calmodulin kinase II activity. The restoration of PFC glutamatergic transmission in stress conditions may enable D₄ receptors to serve as a synaptic stabilizer in normal and pathological conditions.     

Distinct intrinsic and synaptic properties of pre‐sympathetic and pre‐parasympathetic output neurons in Barrington's nucleus

Barrington's nucleus (BN), commonly known as the pontine micturition center, controls micturition and other visceral functions through projections to the spinal cord. In this study, we developed a rat brain slice preparation to determine the intrinsic and synaptic mechanisms regulating pre‐sympathetic output (PSO) and pre‐parasympathetic output (PPO) neurons in the BN using patch‐clamp recordings. The PSO and PPO neurons were retrogradely labeled by injecting fluorescent tracers into the intermediolateral region of the spinal cord at T13‐L1 and S1‐S2 levels, respectively. There were significantly more PPO than PSO neurons within the BN. The basal activity and membrane potential were significantly lower in PPO than in PSO neurons, and A‐type K⁺ currents were significantly larger in PPO than in PSO neurons. Blocking A‐type K⁺ channels increased the excitability more in PPO than in PSO neurons. Stimulting μ‐opioid receptors inhibited firing in both PPO and PSO neurons. The glutamatergic EPSC frequency was much lower, whereas the glycinergic IPSC frequency was much higher, in PPO than in PSO neurons. Although blocking GABA_A receptors increased the excitability of both PSO and PPO neurons, blocking glycine receptors increased the firing activity of PPO neurons only. Furthermore, blocking ionotropic glutamate receptors decreased the excitability of PSO neurons but paradoxically increased the firing activity of PPO neurons by reducing glycinergic input. Our findings indicate that the membrane and synaptic properties of PSO and PPO neurons in the BN are distinctly different. This information improves our understanding of the neural circuitry and central mechanisms regulating the bladder and other visceral organs.     

Effects of Estradiol on Voltage-Gated Potassium Channels in Mouse Dorsal Root Ganglion Neurons

Voltage-gated potassium channels are regulators of membrane potentials, action potential shape, firing adaptation, and neuronal excitability in excitable tissues including in the primary sensory neurons of dorsal root ganglion (DRG). In this study, using the whole-cell patch-clamp technique, the effect of estradiol (E2) on voltage-gated total outward potassium currents, the component currents transient “A-type” current (I _A) currents, and “delayed rectifier type” (I _KDR) currents in isolated mouse DRG neurons was examined. We found that the extracellularly applied 17β-E2 inhibited voltage-gated total outward potassium currents; the effects were rapid, reversible, and concentration-dependent. Moreover, the membrane impermeable E2-BSA was as efficacious as 17β-E2, whereas 17α-E2 had no effect. 17β-E2-stimulated decrease in the potassium current was unaffected by treatment with ICI 182780 (classic estrogen receptor antagonist), actinomycin D (RNA synthesis inhibitor), or cycloheximide (protein synthesis inhibitor). We also found that I _A and I _KDR were decreased after 17β-E2 application. 17β-E2 significantly shifted the activation curve for I _A and I _KDR channels in the hyperpolarizing direction. In conclusion, our results demonstrate that E2 inhibited voltage-gated K⁺ channels in mouse DRG neurons through a membrane ER-activated non-genomic pathway.     

Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model

Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson''s disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.     

Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals

Dopamine input to the striatum is required for voluntary motor movement, behavioral reinforcement, and responses to drugs of abuse. It is speculated that these functions are dependent on either excitatory or inhibitory modulation of corticostriatal synapses onto medium spiny neurons (MSNs). While dopamine modulates MSN excitability, a direct presynaptic effect on the corticostriatal input has not been clearly demonstrated. We combined optical monitoring of synaptic vesicle exocytosis from motor area corticostriatal afferents and electrochemical recordings of striatal dopamine release to directly measure effects of dopamine at the level of individual presynaptic terminals. Dopamine released by either electrical stimulation or amphetamine acted via D2 receptors to inhibit the activity of subsets of corticostriatal terminals. Optical and electrophysiological data suggest that heterosynaptic inhibition was enhanced by higher frequency stimulation and was selective for the least active terminals. Thus, dopamine, by filtering less active inputs, appears to reinforce specific sets of corticostriatal synaptic connections.     

Methyl CpG Binding Protein 2 Gene Disruption Augments Tonic Currents of γ-Aminobutyric Acid Receptors in Locus Coeruleus Neurons: IMPACT ON NEURONAL EXCITABILITY AND BREATHING*

People with Rett syndrome and mouse models show autonomic dysfunction involving the brain stem locus coeruleus (LC). Neurons in the LC of Mecp2-null mice are overly excited, likely resulting from a defect in neuronal intrinsic membrane properties and a deficiency in GABA synaptic inhibition. In addition to the synaptic GABA receptors, there is a group of GABA_A receptors (GABA_ARs) that is located extrasynaptically and mediates tonic inhibition. Here we show evidence for augmentation of the extrasynaptic GABA_ARs in Mecp2-null mice. In brain slices, exposure of LC neurons to GABA_AR agonists increased tonic currents that were blocked by GABA_AR antagonists. With 10 μm GABA, the bicuculline-sensitive tonic currents were ∼4-fold larger in Mecp2-null LC neurons than in the WT. Single-cell PCR analysis showed that the δ subunit, the principal subunit of extrasynaptic GABA_ARs, was present in LC neurons. Expression levels of the δ subunit were ∼50% higher in Mecp2-null neurons than in the WT. Also increased in expression in Mecp2-null mice was another extrasynaptic GABA_AR subunit, α6, by ∼4-fold. The δ subunit-selective agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride and 4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]]benzamide activated the tonic GABA_A currents in LC neurons and reduced neuronal excitability to a greater degree in Mecp2-null mice than in the WT. Consistent with these findings, in vivo application of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride alleviated breathing abnormalities of conscious Mecp2-null mice. These results suggest that extrasynaptic GABA_ARs seem to be augmented with Mecp2 disruption, which may be a compensatory response to the deficiency in GABAergic synaptic inhibition and allows control of neuronal excitability and breathing abnormalities.     

Ionic currents influencing spontaneous firing and pacemaker frequency in dopamine neurons of the ventrolateral periaqueductal gray and dorsal raphe nucleus (vlPAG/DRN): A voltage-clamp and computational modelling study

Dopamine (DA) neurons of the ventrolateral periaqueductal gray (vlPAG) and dorsal raphe nucleus (DRN) fire spontaneous action potentials (APs) at slow, regular patterns in vitro but a detailed account of their intrinsic membrane properties responsible for spontaneous firing is currently lacking. To resolve this, we performed a voltage-clamp electrophysiological study in brain slices to describe their major ionic currents and then constructed a computer model and used simulations to understand the mechanisms behind autorhythmicity in silico. We found that vlPAG/DRN DA neurons exhibit a number of voltage-dependent currents activating in the subthreshold range including, a hyperpolarization-activated cation current (I_H), a transient, A-type, potassium current (I_A), a background, ‘persistent’ (I_NaP) sodium current and a transient, low voltage activated (LVA) calcium current (I_CaLVA). Brain slice pharmacology, in good agreement with computer simulations, showed that spontaneous firing occurred independently of I_H, I_A or calcium currents. In contrast, when blocking sodium currents, spontaneous firing ceased and a stable, non-oscillating membrane potential below AP threshold was attained. Using the DA neuron model we further show that calcium currents exhibit little activation (compared to sodium) during the interspike interval (ISI) repolarization while, any individual potassium current alone, whose blockade positively modulated AP firing frequency, is not required for spontaneous firing. Instead, blockade of a number of potassium currents simultaneously is necessary to eliminate autorhythmicity. Repolarization during ISI is mediated initially via the deactivation of the delayed rectifier potassium current, while a sodium background ‘persistent’ current is essentially indispensable for autorhythmicity by driving repolarization towards AP threshold.     

Scn1a missense mutation impairs GABAA receptor-mediated synaptic transmission in the rat hippocampus

Mutations of the Na_v1.1 channel subunit SCN1A have been implicated in the pathogenesis of human febrile seizures (FS). We have recently developed hyperthermia-induced seizure-susceptible (Hiss) rat, a novel rat model of FS, which carries a missense mutation (N1417H) in Scn1a[1]. Here, we conducted electrophysiological studies to clarify the influences of the Scn1a mutation on the hippocampal synaptic transmission, specifically focusing on the GABAergic system. Hippocampal slices were prepared from Hiss or F344 (control) rats and maintained in artificial cerebrospinal fluid saturated with 95% O₂ and 5% CO₂in vitro. Single neuron activity was recorded from CA1 pyramidal neurons and their responses to the test (unconditioned) or paired pulse (PP) stimulation of the Schaffer collateral/commissural fibers were evaluated. Hiss rats were first tested for pentylenetetrazole-induced seizures and confirmed to show high seizure susceptibility to the blockade of GAGA_A receptors. The Scn1a mutation in Hiss rats did not directly affect spike generation (i.e., number of evoked spikes and firing threshold) of the CA1 pyramidal neurons elicited by the Schaffer collateral/commissural stimulation. However, GABA_A receptor-mediated inhibition of pyramidal neurons by the PP stimulation was significantly disrupted in Hiss rats, yielding a significant increase in the number of PP-induced firings at PP intervals of 32-256 ms. The present study shows that the Scn1a missense mutation preferentially impairs GABA_A receptor-mediated synaptic transmission without directly altering the excitability of the pyramidal neurons in the hippocampus, which may be linked to the pathogenesis of FS.     

Functional organization of dendritic Ca2+ signals in midbrain dopamine neurons

Dendritic Ca²⁺ plays an important role not only in synaptic integration and synaptic plasticity, but also in dendritic excitability in midbrain dopamine neurons. However, the functional organization of dendritic Ca²⁺ signals in the dopamine neurons remains largely unknown. We therefore investigated dendritic Ca²⁺ signals by measuring glutamate-induced Ca²⁺ increases along the dendrites of acutely isolated midbrain dopamine neurons.Maximal doses of glutamate induced a [Ca²⁺]_c rise with similar amplitudes in proximal and distal dendritic regions of a dopamine neuron. Glutamate receptors contributed incrementally to the [Ca²⁺]_c rise according to their distance from the soma, with a reciprocal decrement in the contribution of voltage-operated Ca²⁺ channels (VOCCs). The contribution of AMPA and NMDA receptors increased with dendritic length, but that of metabotropic glutamate receptors decreased. At low doses of glutamate at which spontaneous firing was sustained, the [Ca²⁺]_c rise was higher in the distal than the proximal regions of a dendrite, possibly due to the increased spontaneous firing rate.These results indicate that functional organization of Ca²⁺ signals in the dendrites of dopamine neurons requires different combination of VOCCs and glutamate receptors according to dendritic length, and that regional Ca²⁺ rises in dendrites respond differently to applied glutamate concentration.     

Effects of cholesterol levels on the excitability of rat hippocampal neurons

Changes in the cholesterol levels dynamically alter the microenvironment of the plasma membrane and have been shown to modify functions of ion channels. However, the cellular effect of these modifications is largely unknown. In this report, we demonstrate that cholesterol levels modulate neuronal excitability in rat hippocampal neurons. Reduction of cholesterol levels shortened the duration and increased the firing frequency and peak amplitude of action potentials, while enrichment of cholesterol reversed the effect. Furthermore, we showed that reduction of cholesterol levels increased, while enrichment of cholesterol decreased the amplitude of the delayed rectifier I_K currents. On the other hand, reduction of cholesterol levels slowed down the inactivation of the fast transient I_A currents, but enrichment of cholesterol had no significant effect on the I_A currents. Besides, alteration in cholesterol levels had no significant effect on the action potential in the presence of blockers for both I_K and I_A currents. These observations demonstrate that cholesterol levels bi-directionally regulate the neuronal excitability mainly through modifications of the I_K and I_A currents, suggesting an optimum level of cholesterol for the optimum excitability of neurons. Alterations in the neuronal cholesterol levels have been associated with aging, cognitive decline, neurodegenerative diseases, etc. Therefore, our findings are important for a deeper understanding of the relationship between the cholesterol level and dysfunctions of the brain at the molecular level.     

Neuritin Activates Insulin Receptor Pathway to Up-regulate Kv4.2-mediated Transient Outward K+ Current in Rat Cerebellar Granule Neurons

Neuritin is a new neurotrophic factor discovered in a screen to identify genes involved in activity-dependent synaptic plasticity. Neuritin also plays multiple roles in the process of neural development and synaptic plasticity. The receptors for binding neuritin and its downstream signaling effectors, however, remain unclear. Here, we report that neuritin specifically increases the densities of transient outward K⁺ currents (I_A) in rat cerebellar granule neurons (CGNs) in a time- and concentration-dependent manner. Neuritin-induced amplification of I_A is mediated by increased mRNA and protein expression of Kv4.2, the main α-subunit of I_A. Exposure of CGNs to neuritin markedly induces phosphorylation of ERK (pERK), Akt (pAkt), and mammalian target of rapamycin (pmTOR). Neuritin-induced I_A and increased expression of Kv4.2 are attenuated by ERK, Akt, or mTOR inhibitors. Unexpectedly, pharmacological blockade of insulin receptor, but not the insulin-like growth factor 1 receptor, abrogates the effect of neuritin on I_A amplification and Kv4.2 induction. Indeed, neuritin activates downstream signaling effectors of the insulin receptor in CGNs and HeLa. Our data reveal, for the first time, an unanticipated role of the insulin receptor in previously unrecognized neuritin-mediated signaling.     

Autophagic bias in the striatum

ABSTRACT

Macroautophagy/autophagy is implicated in the maintenance of normal neuronal activity through the regulation of synaptic function and plasticity. However, differences in autophagic degradation within different classes of neurons have not been examined. We have recently demonstrated that autophagy plays very different roles in the two closely related principal neurons of the striatum – the spiny projection neurons of the direct (dSPN) and indirect (iSPN) pathways. Behavioral and electrophysiological experiments revealed that the absence of autophagy in either of these SPN pathways produces unique effects on motor learning, dendritic length, and intrinsic excitability. Specifically, autophagy is required for the normal development of synaptic inputs onto dSPNs, while being required for intrinsic excitability in iSPNs. In iSPNs, this occurs through the regulation of the activity of the KCNJ/Kir2 ion channel, and provides a first demonstration of autophagic control of neuronal intrinsic excitability.