SUMMARY The promise of using reprogrammed human neurons for disease modeling and regenerative medicine relies on the ability to induce patient-derived neurons with high efficiency and subtype-specificity. We have previously shown that ectopic expression of brain-enriched microRNAs (miRNA), miR-9/9* and miR-124 (miR-9/9*-124), promoted direct conversion of human fibroblasts into neurons. Here we show that co-expression of miR-9/9*-124 with transcription factors enriched in the developing striatum, BCL11B (also known as CTIP2), DLX1, DLX2, MYT1L, can guide the conversion of human postnatal and adult fibroblasts into an enriched population of neurons analogous to striatal medium spiny neurons (MSNs). When transplanted in the mouse brain, the reprogrammed human cells persisted in situ for over 6 months, exhibited membrane properties equivalent to native MSNs and extended projections to the anatomical targets of MSNs. These findings highlight the potential of exploiting the synergism between miR-9/9*-124 and transcription factors to generate specific neuronal subtypes.

The relative contributions of glycolysis and oxidative phosphorylation to neuronal presynaptic energy demands are unclear. In rat hippocampal neurons, ATP production by either glycolysis or oxidative phosphorylation alone sustained basal evoked synaptic transmission for up to 20 min. However, combined inhibition of both ATP sources abolished evoked transmission. Neither action potential propagation failure nor depressed Ca 2ϩ influx explained loss of evoked synaptic transmission. Rather, inhibition of ATP synthesis caused massive spontaneous vesicle exocytosis, followed by arrested endocytosis, accounting for the disappearance of evoked postsynaptic currents. In contrast to its weak effects on basal transmission, inhibition of oxidative phosphorylation alone depressed recovery from vesicle depletion. Local astrocytic lactate shuttling was not required. Instead, either ambient monocarboxylates or neuronal glycolysis was sufficient to supply requisite substrate. In summary, basal transmission can be sustained by glycolysis, but strong presynaptic demands are met preferentially by oxidative phosphorylation, which can be maintained by bulk but not local monocarboxylates or by neuronal glycolysis.

Background:The functions of palmitate turnover in signal transduction are poorly understood. Results: Inhibiting palmitate turnover on R7BP redistributed R7BP-R7 RGS complexes from the plasma membrane to endomembranes, dissociated them from GIRK channels, and delayed G i/o deactivation and channel closure. Conclusion: Palmitate turnover on R7BP promotes GIRK channel deactivation. Significance: Inhibiting palmitate turnover on R7BP could enhance GIRK activity in neurological disorders.

Neuron-astrocyte interactions are critical for proper CNS development and function. Astrocytes secrete factors that are pivotal for synaptic development and function, neuronal metabolism, and neuronal survival. Our understanding of this relationship, however, remains incomplete due to technical hurdles that have prevented the removal of astrocytes from neuronal circuits without changing other important conditions. Here we overcame this obstacle by growing solitary rat hippocampal neurons on microcultures that were comprised of either an astrocyte bed (ϩastrocyte) or a collagen bed (Ϫastrocyte) within the same culture dish. ϪAstrocyte autaptic evoked EPSCs, but not IPSCs, displayed an altered temporal profile, which included increased synaptic delay, increased time to peak, and severe glutamate release asynchrony, distinct from previously described quantal asynchrony. Although we observed minimal alteration of the somatically recorded action potential waveform, action potential propagation was altered. We observed a longer latency between somatic initiation and arrival at distal locations, which likely explains asynchronous EPSC peaks, and we observed broadening of the axonal spike, which likely underlies changes to evoked EPSC onset. No apparent changes in axon structure were observed, suggesting altered axonal excitability. In conclusion, we propose that local astrocyte support has an unappreciated role in maintaining glutamate release synchrony by disturbing axonal signal propagation.

The diet of capuchin monkeys consists largely of fruits, but these monkeys commonly prey upon insects and other invertebrates as well as vertebrates such as lizards, birds, and fish. Capturing small fast-moving prey requires the ability to process complex visuospatial information such as motion detection, shape, and pursuit. Here we report the results of an experimental investigation into whether capuchins display sex differences in prey capture efficiency, and whether these differences are associated with the morphology of regions of the corpus callosum (CC) involved in visuospatial ability. We examined the prey capture behavior of seven capuchin subjects (four female, three male) in the laboratory by providing subjects opportunities to fish. Additionally, we obtained structural magnetic resonance images from these subjects to determine if spatial-ability was related to CC anatomy. Over 30 fishing trials, we recorded the number of prey capture attempts, success rate in capturing fish, and hand techniques used in these attempts. Males were significantly faster and more successful than females at capturing prey. In addition, males had smaller total CC:brain ratios than females. Males displayed a left hand bias, as well as significant unimanual usage, whereas females displayed no significant preference for hand usage. Individual capture times were correlated with total CC:brain ratio. Taken together, our results suggest a relationship between prey capture efficiency, sex, and the degree of brain lateralization.