Active dendritic integration as a mechanism for robust and precise grid cell firing.

Understanding how active dendrites are exploited for behaviorally relevant computations is a fundamental challenge in neuroscience. Grid cells in medial entorhinal cortex are an attractive model system for addressing this question, as the computation they perform is clear: they convert synaptic inputs into spatially modulated, periodic firing. Whether active dendrites contribute to the generation of the dual temporal and rate codes characteristic of grid cell output is unknown. We show that dendrites of medial entorhinal cortex neurons are highly excitable and exhibit a supralinear input-output function in vitro, while in vivo recordings reveal membrane potential signatures consistent with recruitment of active dendritic conductances. By incorporating these nonlinear dynamics into grid cell models, we show that they can sharpen the precision of the temporal code and enhance the robustness of the rate code, thereby supporting a stable, accurate representation of space under varying environmental conditions. Our results suggest that active dendrites may therefore constitute a key cellular mechanism for ensuring reliable spatial navigation.

Dopaminergic cell damage and vulnerability to MPTP in Pink1 knockdown zebrafish.

The functions of PTEN (phosphatase/tensin homolog)-induced putative kinase (PINK1), which is mutated in early-onset Parkinson's disease, are poorly understood. We characterized a PINK1 antibody and found colocalization of PINK1-like immunoreactivity with aminergic markers. We inactivated translation of Pink1 using morpholino-oligonucleotides (MOs) in larval zebrafish. Dopaminergic neurons consisted of two sets of neuron populations, marked by complementary expression of two tyrosine hydroxylase genes th1 and th2. Translation inhibition of pink1 resulted in reduction of both th mRNA forms until day 5 or 7, respectively. The affected dopaminergic neurons were in one group expressing th1 and three groups expressing th2. Lack of Pink1 sensitized the fish to subeffective doses of MPTP, which caused a locomotor deficit and facilitated loss of th1 in one diencephalic dopaminergic cell group. Control experiments with pink1 mRNA and control MO suggested that effects with the splice site targeting MO were specific. Distinct groups of dopaminergic neurons are thus sensitive to loss of Pink1. Sensitization of the pink1 morphant fish to MPTP toxicity suggests that genetic factors play a role in toxin-induced Parkinson's disease.

Hyperserotonergic phenotype after monoamine oxidase inhibition in larval zebrafish.

Serotonin (or 5-hydroxytryptamine; 5-HT) and monoamine oxidase (MAO) are involved in several physiological functions and pathological conditions. We show that the serotonergic system and its development in zebrafish are similar to those of other vertebrates rendering zebrafish a good model to study them. Development of MAO expression followed a similar time course as the 5-HT system. MAO expression and activity were located in or adjacent to serotonergic nuclei and their targets, especially in the ventral hypothalamus. MAO mRNA was detected in the brain from 24 h post-fertilization and histochemical enzyme activity from 42 h post-fertilization. Deprenyl (100 microM) decreased MAO activity 34-74% depending on the age. Inhibition of MAO by deprenyl strongly increased 5-HT but not dopamine and noradrenaline levels. Deprenyl decreased 5-HT-immunoreactivity in serotonergic neurons and induced novel ectopic 5-HT-immunoreactivity neurons in the diencephalon in a manner dependent on 5-HT uptake. Deprenyl administration decreased locomotion, altered vertical positioning and increased heart rate. Treatment with p-chlorophenylalanine normalized 5-HT levels and rescued the behavioral alteration, indicating that the symptoms were 5-HT dependent. These findings suggest that zebrafish MAO resembles mammalian MAO A more than MAO B, metabolizing mainly 5-HT. Applications of this model of hyperserotonergism include pharmacological and genetic screenings.