Synchronous recruitment of fast-spiking (FS) parvalbumin (PV) interneurons generates gamma oscillations, rhythms that emerge during performance of cognitive tasks. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists alters gamma rhythms, and can induce cognitive as well as psychosis-like symptoms in humans. The disruption of NMDA receptor (NMDAR) signaling specifically in FS PV interneurons is therefore hypothesized to give rise to neural network dysfunction that could underlie these symptoms. To address the connection between NMDAR activity, FS PV interneurons, gamma oscillations and behavior, we generated mice lacking NMDAR neurotransmission only in PV cells (PV-Cre/NR1f/f mice). Here, we show that mutant mice exhibit enhanced baseline cortical gamma rhythms, impaired gamma rhythm induction after optogenetic drive of PV interneurons and reduced sensitivity to the effects of NMDAR antagonists on gamma oscillations and stereotypies. Mutant mice show largely normal behaviors except for selective cognitive impairments, including deficits in habituation, working memory and associative learning. Our results provide evidence for the critical role of NMDAR in PV interneurons for expression of normal gamma rhythms and specific cognitive behaviors.

Spinal cord injury often results in permanent functional impairment. Neural stem cells present in the adult spinal cord can be expanded in vitro and improve recovery when transplanted to the injured spinal cord, demonstrating the presence of cells that can promote regeneration but that normally fail to do so efficiently. Using genetic fate mapping, we show that close to all in vitro neural stem cell potential in the adult spinal cord resides within the population of ependymal cells lining the central canal. These cells are recruited by spinal cord injury and produce not only scar-forming glial cells, but also, to a lesser degree, oligodendrocytes. Modulating the fate of ependymal progeny after spinal cord injury may offer an alternative to cell transplantation for cell replacement therapies in spinal cord injury. Spinal cord injuries occur in more than 30.000 individuals each year worldwide and result in significant morbidity, with patients requiring long physical and medical care. The recent identification of resident stem cells in the adult spinal cord has opened up for the possibility of pharmacological manipulation of these cells to produce cell types promoting recovery after injury. We have employed genetic tools to specifically address the identity and reaction to injury of a spinal cord subpopulation of cells known as ependymal cell. Genetic labeling of this putative stem cell population allows for the evaluation of stem cell activity in vitro and in vivo. We found that ependymal cells lining the central canal act as neural stem cells in vitro and contribute extensively to the glial scar in vivo. Interestingly, injury induces proliferation of ependymal cells and migration of ependyma-derived progeny towards the site of injury. Moreover, ependymal cell progeny differentiate and give rise to astrocytes as well as myelinating oligodendrocytes. In summary, our results point to ependymal cells as an attractive candidate population for non-invasive manipulation after injury.

A major long-term goal of systems neuroscience is to identify the different roles of neural subtypes in brain circuit function. The ability to causally manipulate selective cell types is critical to meeting this goal. This protocol describes techniques for optically stimulating specific populations of excitatory neurons and inhibitory interneurons in vivo in combination with electrophysiology. Cell type selectivity is obtained using Cre-dependent expression of the light-activated channel Channelrhodopsin-2. We also describe approaches for minimizing optical interference with simultaneous extracellular and intracellular recording. These optogenetic techniques provide a spatially and temporally precise means of studying neural activity in the intact brain and allow a detailed examination of the effect of evoked activity on the surrounding local neural network. Injection of viral vectors requires 30–45 min, and in vivo electrophysiology with optogenetic stimulation requires 1–4 h.

Parvalbumin-expressing interneurons regulate the activation and fate choice of adult neural stem cells. The mammalian brain is capable of generating new nerve cells into adulthood and has a number of specialized stem-cell niches for the purpose. Previous studies have examined the mechanisms that regulate the late stages of adult neurogenesis, but little is known about how quiescent neural stem cells are regulated. Here, Juan Song and colleagues use genetic and optogenetic methods to demonstrate a role for parvalbumin-expressing (PV1) interneurons, but not other inhibitory neuron subtypes, in driving fate decisions for radial glia-like quiescent neural stem cells in the adult mouse hippocampus. The study identifies a niche cell–signal–receptor trio and local circuits that provide a mechanism through which quiescent adult neural stem cells can undergo activation and self-renewal in response to neuronal activity and experience. Adult neurogenesis arises from neural stem cells within specialized niches1,2,3. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival1,3. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells4,5,6,7,8,9 (RGLs) respond tonically to the neurotransmitter γ-aminobutyric acid (GABA) by means of γ2-subunit-containing GABAA receptors. Clonal analysis9 of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of γ2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division8. Our study identifies a niche cell–signal–receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.