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Midbrain-derived neurotrophins support survival of immature striatal projection neurons.

ABSTRACT: Neuronal death occurs at several stages during embryogenesis and early postnatal development; however, it is unknown how the survival of immature neurons at their origin is regulated before these cells migrate to their final destination. Striatal projection neurons, known as medium-sized spiny neurons (MSNs), in both the direct and indirect pathways are generated in the lateral ganglionic eminence (LGE). Here we report that brain-derived neurotrophic factor and neurotrophin-3 are anterogradely transported from midbrain dopaminergic neurons and support the survival of immature MSNs of the indirect and direct pathways, respectively, in the developing mouse striatum and LGE. These results reveal a novel mode of neurotrophic action in the nervous system by linking neurotrophins to the survival of immature neurons at their origin, while also suggesting that innervating neurons may control the size of their targeting neuronal population in the brain.

SUBMITTER: Baydyuk M

PROVIDER: S-EPMC3711532 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Midbrain-derived neurotrophins support survival of immature striatal projection neurons.

Baydyuk Maryna M Xie Yuxiang Y Tessarollo Lino L Xu Baoji B

The Journal of neuroscience : the official journal of the Society for Neuroscience 20130201 8

Neuronal death occurs at several stages during embryogenesis and early postnatal development; however, it is unknown how the survival of immature neurons at their origin is regulated before these cells migrate to their final destination. Striatal projection neurons, known as medium-sized spiny neurons (MSNs), in both the direct and indirect pathways are generated in the lateral ganglionic eminence (LGE). Here we report that brain-derived neurotrophic factor and neurotrophin-3 are anterogradely t ...[more]

PMID: 23426664

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Project description:Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DANs), and Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson's disease (PD) patients. Here, we obtained well-characterized DANs from hESCs and transplanted them into two parkinsonian monkeys to assess their behavioral and imaging changes. DANs from hESCs expressed dopaminergic markers, generated action potentials, and released dopamine (DA) in vitro. These neurons were transplanted bilaterally into the putamen of parkinsonian NHPs, and using magnetic resonance imaging techniques, we calculated the fractional anisotropy (FA) and mean diffusivity (MD), both employed for the first time for these purposes, to detect in vivo axonal and cellular density changes in the brain. Likewise, positron-emission tomography scans were performed to evaluate grafted DANs. Histological analyses identified grafted DANs, which were quantified stereologically. After grafting, animals showed signs of partially improved motor behavior in some of the HALLWAY motor tasks. Improvement in motor evaluations was inversely correlated with increases in bilateral FA. MD did not correlate with behavior but presented a negative correlation with FA. We also found higher 11C-DTBZ binding in positron-emission tomography scans associated with grafts. Higher DA levels measured by microdialysis after stimulation with a high-potassium solution or amphetamine were present in grafted animals after ten months, which has not been previously reported. Postmortem analysis of NHP brains showed that transplanted DANs survived in the putamen long-term, without developing tumors, in immunosuppressed animals. Although these results need to be confirmed with larger groups of NHPs, our molecular, behavioral, biochemical, and imaging findings support the integration and survival of human DANs in this pre-clinical PD model.

Project description:Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs. Measurements of this disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feedforward inhibition. Moreover, functional nAChRs are also present on populations of GINs that respond only weakly to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices from mice we show that upon synchronous optogenetic activation of corticostriatal projections blockade of α4β2 nAChRs shortened SPN spike latencies and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond strongly to phasic CIN activation. In particular, the observed decrease in spike latency caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, a parallel hyperpolarization of PV-FSIs, and was occluded by pharmacologically preventing cortical activation of PV-FSIs. Taken together, we describe a role for tonic (as opposed to phasic) activation of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs maintains a GABAergic brake on cortically-driven striatal output by 'priming' feedforward inhibition, a process that may shape SPN spike timing, striatal processing, and synaptic plasticity.

Dataset Information

Midbrain-derived neurotrophins support survival of immature striatal projection neurons.

Publications

Midbrain-derived neurotrophins support survival of immature striatal projection neurons.

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