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Signalling Pathways Mediating the Effects of CD40-Activated CD40L Reverse Signalling on Inhibitory Medium Spiny Neuron Neurite Growth.

ABSTRACT: CD40-activated CD40L-mediated reverse signalling is a major physiological regulator of neurite growth from excitatory and inhibitory neurons in the developing central nervous system (CNS). Whereas in excitatory pyramidal neurons, CD40L reverse signalling promotes the growth and elaboration of dendrites and axons, in inhibitory GABAergic striatal medium spiny neurons (MSNs), it restricts neurite growth and branching. In pyramidal neurons, we previously reported that CD40L reverse signalling activates an interconnected and interdependent signalling network involving protein kinase C (PKC), extracellular regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK) signalling pathways that regulates dendrite and axon growth. Here, we have studied whether these signalling pathways also influence neurite growth from striatal inhibitory MSNs. To unequivocally activate CD40L reverse signalling, we treated MSN cultures from CD40-deficient mice with CD40-Fc. Here, we report that activation of CD40L reverse signalling in these cultures also increased the phosphorylation of PKC, ERK1/2, and JNK. Using pharmacological activators and inhibitors of these signalling pathways singularly and in combination, we have shown that, as in pyramidal neurons, these signalling pathways work in an interconnected and interdependent network to regulate the neurite growth, but their functions, relationships, and interdependencies are different from those observed in pyramidal neurons. Furthermore, immunoprecipitation studies showed that stimulation of CD40L reverse signalling recruits the catalytic fragment of Syk tyrosine kinase, but in contrast to pyramidal neurons, PKC does not participate in this recruitment. Our findings show that distinctive networks of three signalling pathways mediate the opposite effects of CD40L reverse signalling on neurite growth in excitatory and inhibitory neurons.

SUBMITTER: Carriba P

PROVIDER: S-EPMC8067729 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Slowly varying activity in the striatum, the main Basal Ganglia input structure, is important for the learning and execution of movement sequences. Striatal medium spiny neurons (MSNs) form cell assemblies whose population firing rates vary coherently on slow behaviourally relevant timescales. It has been shown that such activity emerges in a model of a local MSN network but only at realistic connectivities of 10 ~ 20% and only when MSN generated inhibitory post-synaptic potentials (IPSPs) are realistically sized. Here we suggest a reason for this. We investigate how MSN network generated population activity interacts with temporally varying cortical driving activity, as would occur in a behavioural task. We find that at unrealistically high connectivity a stable winners-take-all type regime is found where network activity separates into fixed stimulus dependent regularly firing and quiescent components. In this regime only a small number of population firing rate components interact with cortical stimulus variations. Around 15% connectivity a transition to a more dynamically active regime occurs where all cells constantly switch between activity and quiescence. In this low connectivity regime, MSN population components wander randomly and here too are independent of variations in cortical driving. Only in the transition regime do weak changes in cortical driving interact with many population components so that sequential cell assemblies are reproducibly activated for many hundreds of milliseconds after stimulus onset and peri-stimulus time histograms display strong stimulus and temporal specificity. We show that, remarkably, this activity is maximized at striatally realistic connectivities and IPSP sizes. Thus, we suggest the local MSN network has optimal characteristics - it is neither too stable to respond in a dynamically complex temporally extended way to cortical variations, nor is it too unstable to respond in a consistent repeatable way. Rather, it is optimized to generate stimulus dependent activity patterns for long periods after variations in cortical excitation.

Project description:The classical motor symptoms of Parkinson's disease (PD) are caused by degeneration of dopaminergic neurons in the substantia nigra, which is followed by secondary dendritic pruning and spine loss at striatal medium spiny neurons (MSN). We hypothesize that these morphological changes at MSN underlie at least in part long-term motor complications in PD patients. In order to define the potential benefits and limitations of dopamine substitution, we tested in a mouse model whether dendritic pruning and spine loss can be reversible when dopaminergic axon terminals regenerate. In order to induce degeneration of nigrostriatal dopaminergic neurons we used the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6J mice; 30 mg/kg MPTP was applied i.p. on five consecutive days. In order to assess the consequences of dopamine depletion, mice were analyzed 21 days after the last injection. In order to test reversibility of MSN changes we exploited the property of this model that striatal axon terminals regenerate by sprouting within 90 days and analyzed a second cohort 90 days after MPTP. Degeneration of dopaminergic neurons was confirmed by counting TH-positive neurons in the substantia nigra and by analyzing striatal catecholamines. Striatal catecholamine recovered 90 days after MPTP. MSN morphology was visualized by Golgi staining and quantified as total dendritic length, number of dendritic branch points, and density of dendritic spines. All morphological parameters of striatal MSN were reduced 21 days after MPTP. Statistical analysis indicated that dendritic pruning and the reduction of spine density represent two distinct responses to dopamine depletion. Ninety days after MPTP, all morphological changes recovered. Our findings demonstrate that morphological changes in striatal MSN resulting from dopamine depletion are reversible. They suggest that under optimal conditions, symptomatic dopaminergic therapy might be able to prevent maladaptive plasticity and long-term motor complications in PD patients.

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Signalling Pathways Mediating the Effects of CD40-Activated CD40L Reverse Signalling on Inhibitory Medium Spiny Neuron Neurite Growth.

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