Biology subjects

Panula, P.

Publications and source records attributed to Panula, P..

3 recordsLinked to original sources

bioRxiv2018

Regeneration of dopaminergic neurons in adult zebrafish depends on immune system activation and differs for distinct populations

Adult zebrafish regenerate neurons in their brain, but the extent and variability of this capacity is unclear. Here we ask whether loss of various dopaminergic neuron populations is sufficient to trigger their functional regeneration. Genetic lineage tracing shows that specific diencephalic ependymo-radial glial progenitor cells (ERGs) give rise to new dopaminergic (Th+) neurons. Ablation elicits an immune response, increased proliferation of ERGs and increased addition of new Th+ neurons in populations that constitutively add new neurons, e.g. diencephalic population 5/6. Inhibiting the immune response attenuates neurogenesis to control levels. Boosting the immune response enhances ERG proliferation, but not addition of Th+ neurons. In contrast, in populations in which constitutive neurogenesis is undetectable, e.g. the posterior tuberculum and locus coeruleus, cell replacement and tissue integration are incomplete and transient. This is associated with loss of spinal Th+ axons, as well as permanent deficits in shoaling and reproductive behaviour. Hence, dopaminergic neuron populations in the adult zebrafish brain show vast differences in regenerative capacity that correlate with constitutive addition of neurons and depend on immune system activation.

neuroscience↗

bioRxiv2017

Loss Of lrrk2 Impairs Cell Proliferation And Neuronal Regeneration In The Zebrafish Brain

LRRK2 mutations are a major cause of Parkinsons disease. Pathogenicity of LRRK2 loss-of-function is controversial, as knockout in rodents reportedly induces no brain-specific effects and knockdown studies in zebrafish are conflicting. Here we show that CRISPR/Cas9-engineered deletion of the ~60-kbp-long zebrafish lrrk2 locus elicits a pleomorphic, albeit transient brain phenotype in maternal-zygotic mutants (mzLrrk2). Intriguingly, 11-month-old mzLrrk2 adults display increased dopamine and serotonin catabolism. Additionally, we find decreased mitosis in the larval brain and reduced stab injury-induced neuronal regeneration in the adult telencephalon. Finally, hypokinesia associates with loss of lrrk2 in larvae. Our results demonstrate that lrrk2 knockout has an early neurodevelopmental effect, and leads to perturbed dopamine and serotonin catabolism in a LRRK2 knockout. We propose mzLrrk2 zebrafish as a valuable tool to study LRRK2 loss-of-function in vivo, and provide a link between LRRK2 and the control of basal cell proliferation in the brain that may become potentially critical upon challenges like brain injury.

neuroscience↗

bioRxiv2017

Neurotrophin Receptor Ntrk2b Function In The Maintenance Of Dopamine And Serotonin Neurons In Zebrafish

Brain-derived neurotrophic factor (BDNF), together with its cognate receptor tyrosine kinase B (TrkB), plays an essential role in the development and plasticity of the brain and is widely implicated in psychiatric diseases (Autry and Monteggia, 2012). Due to the highly conserved evolutionary lineage of neurotrophins and their receptors in vertebrates, the zebrafish is a well-suited model for this study. The TrkB receptor, also known as NTRK2, has two forms in zebrafish, Ntrk2a and Ntrk2b. The spatio-temporal expression pattern of bdnf and ntrk2b in zebrafish was studied using in situ hybridization. The complementary expression pattern of ntrk2b to bdnf suggests that ntrk2b is the key receptor, unlike its duplicate isoform ntrk2a. Two reverse genetics strategies, morpholino oligonucleotides (MO) and the TILLING mutant, were applied in this study. The loss or complete deletion of ntrk2b had no major effect on the viability, gross phenotype, or swimming behavior of zebrafish. A specific subset of the dopaminergic and serotonergic neuronal population was affected in the morphants and mutants. Downstream signaling transcripts such as bdnf, serta, th2, and tph2 were downregulated and could be rescued by overexpression of the full-length ntrk2b mRNA in the morphants. Pharmacological intervention with a tyrosine kinase inhibitor, K252a, resulted in similar phenotypes. Overall, our results reveal a specific effect of ntrk2b on the two crucial aminergic systems involved in psychiatric disorders and provide an essential tool to study neurotrophin function in modulating neuronal plasticity in the central nervous system.\n\nSignificance StatementBrain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tyrosine kinase (TrkB/NTRK2), play a major role in regulating the development and plasticity of neural circuits. Additionally, BDNF/TrkB signaling is involved in psychiatric disorders and antidepressant responses. This study presents the complementary gene expression pattern of TrkB and BDNF in zebrafish during the early larval stage and in the adult brain. Our results consistently indicate that BDNF/TrkB signaling has a significant role in the development and maintenance of dopaminergic and serotonergic neuronal populations. Therefore, the ntrk2b-deficient zebrafish model is well suited to studying psychiatric disorders attributed to a dysfunctional monoaminergic system, and could potentially be a valuable model for small molecule drug screening.

neuroscience↗