cjun n terminal kinase jnk mediates cortico striatal signaling in a model of parkinson s disease

Abstract The cJun N-terminal kinase (JNK) signaling pathway has been extensively studied with regard to its involvement in neurodegenerative processes, but little is known about its functions in neurotransmission. In a mouse model of Parkinson's disease (PD), we show that the pharmacological activation of dopamine D1 receptors (D1R) produces a large increase in JNK phosphorylation. This effect is secondary to dopamine depletion, and is restricted to the striatal projection neurons that innervate directly the output structures of the basal ganglia (dSPN). Activation of JNK in dSPN relies on cAMP-induced phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), but does not require N -methyl- d -aspartate (NMDA) receptor transmission. Electrophysiological experiments on acute brain slices from PD mice show that inhibition of JNK signaling in dSPN prevents the increase in synaptic strength caused by activation of D1Rs. Together, our findings show that dopamine depletion confers to JNK the ability to mediate dopamine transmission, informing the future development of therapies for PD

Inhibition of IL-1β signaling normalizes NMDA-dependent neurotransmission and reduces seizure susceptibility in a mouse model of Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder caused by prion protein (PrP) misfolding, clinically recognized by cognitive and motor deficits, electroencephalographic abnormalities, and seizures. Its neurophysiological bases are not known. To assess the potential involvement of NMDA receptor (NMDAR) dysfunction, we analyzed NMDA-dependent synaptic plasticity in hippocampal slices from Tg(CJD) mice, which model a genetic form of CJD. Because PrP depletion may result in functional upregulation of NMDARs, we also analyzed PrP knock-out (KO) mice. Long-term potentiation (LTP) at the Schaffer collateral-commissural synapses in the CA1 area of ∼100-d-old Tg(CJD) mice was comparable to that of wild-type (WT) controls, but there was an inversion of metaplasticity, with increased GluN2B phosphorylation, which is indicative of enhanced NMDAR activation. Similar but less marked changes were seen in PrP KO mice. At ∼300 d of age, the magnitude of LTP increased in Tg(CJD) mice but decreased in PrP KO mice, indicating divergent changes in hippocampal synaptic responsiveness. Tg(CJD) but not PrP KO mice were intrinsically more susceptible than WT controls to focal hippocampal seizures induced by kainic acid. IL-1β-positive astrocytes increased in the Tg(CJD) hippocampus, and blocking IL-1 receptor signaling restored normal synaptic responses and reduced seizure susceptibility. These results indicate that alterations in NMDA-dependent glutamatergic transmission in Tg(CJD) mice do not depend solely on PrP functional loss. Moreover, astrocytic IL-1β plays a role in the enhanced synaptic responsiveness and seizure susceptibility, suggesting that targeting IL-1β signaling may offer a novel symptomatic treatment for CJD.SIGNIFICANCE STATEMENT Dementia and myoclonic jerks develop in individuals with Creutzfeldt-Jakob disease (CJD), an incurable brain disorder caused by alterations in prion protein structure. These individuals are prone to seizures and have high brain levels of the inflammatory cytokine IL-1β. Here we show that blocking IL-1β receptors with anakinra, the human recombinant form of the endogenous IL-1 receptor antagonist used to treat rheumatoid arthritis, normalizes hippocampal neurotransmission and reduces seizure susceptibility in a CJD mouse model. These results link neuroinflammation to defective neurotransmission and the enhanced susceptibility to seizures in CJD and raise the possibility that targeting IL-1β with clinically available drugs may be beneficial for symptomatic treatment of the disease

Opposite responses to aversive stimuli in lateral habenula neurons

Appropriate behavioural strategies to cope with unexpected salient stimuli require synergistic neuronal responses in diverse brain regions. Among them, the epithalamic lateral habenula (LHb) plays a pivotal role in processing salient stimuli of aversive valence. Integrated in the complex motivational circuit, LHb neurons are indeed excited by aversive stimuli, including footshock (Fs). However, whether such excitation is a common feature represented throughout the LHb remains unclear. Here, we combined single-unit extracellular recordings in anaesthetized mice with juxtacellular labelling to describe the nature, location and pharmacological properties of Fs-driven responses within the LHb. We find that, along with Fs-excited cells, about 10% of LHb neurons display Fs-mediated inhibitory responses. Such inhibited neuronal population, in contrast to Fs-excited neurons, display regular and high frequency activity at baseline and is clustered in the medial portion of the LHb. Juxtacellular labelling of Fs-excited and inhibited neurons unravels that both populations are of glutamatergic type, as they co-localized with the EAAC1 glutamatergic transporter but not with the GAD67 GABAergic marker. Moreover, while the excitatory responses to Fs require both AMPA and NMDA receptors, the inhibitory responses rely instead on GABAA channels. Taken together, our results indicate that two functionally and partly segregated LHb neuronal ensembles encode Fs in an opposite fashion. This highlights the neuronal complexity in the LHb for processing aversive external stimuli

Opposite responses to aversive stimuli in lateral habenula neurons

Appropriate behavioural strategies to cope with unexpected salient stimuli require synergistic neuronal responses in diverse brain regions. Among them, the epithalamic lateral habenula (LHb) plays a pivotal role in processing salient stimuli of aversive valence. Integrated in the complex motivational circuit, LHb neurons are indeed excited by aversive stimuli, including footshock (Fs). However, whether such excitation is a common feature represented throughout the LHb remains unclear. Here, we combined single-unit extracellular recordings in anaesthetized mice with juxtacellular labelling to describe the nature, location and pharmacological properties of Fs-driven responses within the LHb. We find that, along with Fs-excited cells, about 10% of LHb neurons display Fs-mediated inhibitory responses. Such inhibited neuronal population, in contrast to Fs-excited neurons, display regular and high frequency activity at baseline and is clustered in the medial portion of the LHb. Juxtacellular labelling of Fs-excited and inhibited neurons unravels that both populations are of glutamatergic type, as they co-localized with the EAAC1 glutamatergic transporter but not with the GAD67 GABAergic marker. Moreover, while the excitatory responses to Fs require both AMPA and NMDA receptors, the inhibitory responses rely instead on GABAA channels. Taken together, our results indicate that two functionally and partly segregated LHb neuronal ensembles encode Fs in an opposite fashion. This highlights the neuronal complexity in the LHb for processing aversive external stimuli

Excitatory serotonergic signaling regulates synaptic plasticity at striatal glutamatergic inputs

The dorsal striatum receives glutamatergic cortical and thalamic afferents, which are extensively modulated by monoaminergic inputs, such as dopamine and serotonin (5-HT). Various models have been proposed regarding the interactions between reward and punishment, with serotonin closely associated with learning of negative events, and countervailing dopamine regulation of corticostriatal circuits and reward. Recent evidence has challenged this view, suggesting that 5-HT signaling can synergize with dopamine signaling to shape reward-guided behavior. However, the molecular and synaptic correlates of this behavioral role of 5-HT at striatal circuits remain to be established. In the dorsolateral striatum, we found that the chemogenetic inhibition of 5-HT release resulted in a spike-timing-dependent form of long-term depression (t-LTD) at glutamatergic synapses on striatal projection neurons of the direct pathway (dSPNs). These synaptic effects of chemogenetic inhibition of 5-HT release were recapitulated by the pharmacological inhibition of the Gs-coupled 5-HT4 receptor subtype (5-HT4R). t-LTD is independent from endocannabinoid signaling, shows a postsynaptic locus of expression, and it is associated with an increased dendritic Ca2+ signal. Additionally, optogenetic interrogation of glutamatergic inputs to dSPNs indicated that this form of t-LTD is expressed at thalamostriatal synapses. Inhibiting in-vivo 5-HT4R during instrumental conditioning of nose-poke for food reward affected goal-directed control of behavior, thus supporting the role of striatal 5-HT signaling in mediating aspects of reward-guided behavior

Coordinated Regulation of Synaptic Plasticity at Striatopallidal and Striatonigral Neurons Orchestrates Motor Control

The basal ganglia play a critical role in shaping motor behavior. For this function, the activity of medium spiny neurons (MSNs) of the striatonigral and striatopallidal pathways must be integrated. It remains unclear whether the activity of the two pathways is primarily coordinated by synaptic plasticity mechanisms. Using a model of Parkinson’s disease, we determined the circuit and behavioral effects of concurrently regulating cell-type-specific forms of corticostriatal long-term synaptic depression (LTD) by inhibiting small-conductance Ca2+-activated K+ channels (SKs) of the dorsolateral striatum. At striatopallidal synapses, SK channel inhibition rescued the disease-linked deficits in endocannabinoid (eCB)-dependent LTD. At striatonigral cells, inhibition of these channels counteracted a form of adenosine-mediated LTD by activating the ERK cascade. Interfering with eCB-, adenosine-, and ERK signaling in vivo alleviated motor abnormalities, which supports that synaptic modulation of striatal pathways affects behavior. Thus, our results establish a central role of coordinated synaptic plasticity at MSN subpopulations in motor control

Internalization of Carbon Nano-onions by Hippocampal Cells Preserves Neuronal Circuit Function and Recognition Memory

One area where nanomedicine may offer superior performances and efficacy compared to current strategies is in the diagnosis and treatment of central nervous system (CNS) diseases. However, the application of nanomaterials in such complex arenas is still in its infancy and an optimal vector for the therapy of CNS diseases has not been identified. Graphitic carbon nano-onions (CNOs) represent a class of carbon nanomaterials that shows promising potential for biomedical purposes. To probe the possible applications of graphitic CNOs as a platform for therapeutic and diagnostic interventions on CNS diseases, fluorescently labeled CNOs were stereotaxically injected in vivo in mice hippocampus. Their diffusion within brain tissues and their cellular localization were analyzed ex vivo by confocal microscopy, electron microscopy, and correlative light-electron microscopy techniques. The subsequent fluorescent staining of hippocampal cells populations indicates they efficiently internalize the nanomaterial. Furthermore, the inflammatory potential of the CNOs injection was found comparable to sterile vehicle infusion, and it did not result in manifest neurophysiological and behavioral alterations of hippocampal-mediated functions. These results clearly demonstrate that CNOs can interface effectively with several cell types, which encourages further their development as possible brain disease-targeted diagnostics or therapeutics nanocarriers

Internalization of Carbon Nano-onions by Hippocampal Cells Preserves Neuronal Circuit Function and Recognition Memory

One area where nanomedicine may offer superior performances and efficacy compared to current strategies is in the diagnosis and treatment of central nervous system (CNS) diseases. However, the application of nanomaterials in such complex arenas is still in its infancy and an optimal vector for the therapy of CNS diseases has not been identified. Graphitic carbon nano-onions (CNOs) represent a class of carbon nanomaterials that shows promising potential for biomedical purposes. To probe the possible applications of graphitic CNOs as a platform for therapeutic and diagnostic interventions on CNS diseases, fluorescently labeled CNOs were stereotaxically injected in vivo in mice hippocampus. Their diffusion within brain tissues and their cellular localization were analyzed ex vivo by confocal microscopy, electron microscopy, and correlative light-electron microscopy techniques. The subsequent fluorescent staining of hippocampal cells populations indicates they efficiently internalize the nanomaterial. Furthermore, the inflammatory potential of the CNOs injection was found comparable to sterile vehicle infusion, and it did not result in manifest neurophysiological and behavioral alterations of hippocampal-mediated functions. These results clearly demonstrate that CNOs can interface effectively with several cell types, which encourages further their development as possible brain disease-targeted diagnostics or therapeutics nanocarriers

Serotonergic Signaling Controls Input-Specific Synaptic Plasticity at Striatal Circuits

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