Sparsification of AP firing in adult-born hippocampal granule cells via voltage-dependent α5-GABAA receptors.

GABA can depolarize immature neurons close to the action potential (AP) threshold in development and adult neurogenesis. Nevertheless, GABAergic synapses effectively inhibit AP firing in newborn granule cells of the adult hippocampus as early as two weeks post-mitosis. The underlying mechanisms are largely unclear. Here, we analyze GABAergic inputs in newborn hippocampal granule cells mediated by soma-targeting parvalbumin and dendrite-targeting somatostatin interneurons. Surprisingly, both interneuron subtypes activate α5-subunit-containing GABAA receptors (α5-GABAARs) in young neurons, showing a nonlinear voltage dependence with increasing conductance around the AP threshold. By contrast, in mature cells, parvalbumin interneurons mediate linear GABAergic synaptic currents lacking α5-subunits, while somatostatin interneurons continue to target nonlinear α5-GABAARs. Computational modeling shows that the voltage-dependent amplification of α5-GABAAR opening in young neurons is crucial for inhibition of AP firing to generate balanced and sparse firing activity, even with depolarized GABA reversal potential.

Synaptic properties of newly generated granule cells support sparse coding in the adult hippocampus.

In the adult hippocampus new neurons are continuously generated throughout life and integrate into the existing network via the formation of thousands of new synapses. Adult-born granule cells are known to improve learning and memory at about 3-6 weeks post mitosis by enhancing the brains ability to discriminate similar memory items. However, the underlying mechanisms are still controversial. Here we review the distinct functional properties of the newborn young neurons, including enhanced excitability, reduced GABAergic inhibition, NMDA-receptor dependent electrogenesis and enhanced synaptic plasticity. Although these cellular properties provide a competitive advantage for synapse formation, they do not generate 'hyperactivity' of young neurons. By contrast, in vivo evidence from immediate early gene expression and calcium imaging indicates that young neurons show sparse activity during learning. Similarly, in vitro data show a low number of high-impact synapses, leading to activation young cells by distinct subsets of afferent fibers with minimal overlap. Overall, the enhanced excitability of young cells does not generate hyperactivity but rather counterbalance the low number of excitatory input synapses. Finally, sparse coding in young neurons has been shown to be crucial for neurogenesis-dependent improvement of learning behavior. Taken together, converging evidence from cell physiology and behavioral studies suggests a mechanism that can explain the beneficial effects of adult neurogenesis on brain function.

Design and construction of a low-cost nose poke system for rodents.

Operant behavioral tasks for animals have long been used to probe the function of multiple brain regions (i.e., understanding the role of dopamine in electrical brain stimulation reward [1], or determining the rewarding properties of feeding oriented brain pathways [2]). The recent development of tools and techniques has opened the door to refine the answer to these same questions with a much higher degree of specificity and accuracy, both in biological and spatial-temporal terms [3], [4]. A variety of systems designed to test operant behavior are now commercially available, but have prohibitive costs. Here, we provide a low-cost alternative to a nose poke system for mice. Adapting a freely available sketch for ARDUINO boards, in combination with an in-house built PVC box and inexpensive electronic material we constructed a four-port nose poke system that detects and counts port entries. To verify the applicability and validity of our system we tested the behavior of DAT-CRE transgenic mice injected with an adeno-associated virus to express ChannelRhodopsin 2 in the Ventral tegmental area (VTA) and used the BNC output to drive a blue laser coupled to a fiber implanted above the VTA. Over 6 days, mice perform as it has been reported previously [5] exhibiting a remarkable preference for the port that triggers optogenetic stimulation of VTA dopamine neurons. •We provide a low cost alternative to commercially available nose poke system.•Our custom made apparatus is open source and TTL compatible.•We validate our system with optogenetic self-stimulation of dopamine neurons.