Review summary (print version)Background Fast-spiking, parvalbumin-expressing interneurons (PV + interneurons) play a key role in several functions of the brain. They contribute to feedback and feedforward inhibition, and are critically involved in the generation of network oscillations. A hallmark property of these interneurons is speed. In essence, these cells convert an excitatory input signal into an inhibitory output signal within a millisecond. How these remarkable signaling properties are implemented at the molecular and cellular level has been unclear. Furthermore, how PV + interneurons shape complex network functions has remained an open question. Advances Outlook PV+ interneurons may also play a key role in numerous brain diseases. These include epilepsy, but also complex psychiatric diseases, such as schizophrenia. Thus, PV + interneurons may become important therapeutic targets in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will have a chance to successfully use PV + interneurons for therapeutic purposes. 3 Full article (online) AbstractThe success story of fast-spiking, parvalbumin-expressing (PV + ) GABAergic interneurons is amazing. In 1995, the properties of these interneurons were completely unknown. 20 years later, thanks to the massive use of subcellular patchclamp techniques, simultaneous multiple-cell recording, optogenetics, in vivo measurements, and computational approaches, our knowledge about PV + interneurons became more extensive than for several types of pyramidal neurons (Box 1). These findings have implications beyond the "small world" of basic research on GABAergic cells. For example, the results provide a first proof of principle that neuroscientists might be able to close the gaps between molecular, cellular, network, and behavioral level, which represents one of the main challenges at the present time. Furthermore, the results may form the basis for using PV + interneurons as therapeutical targets for brain diseases in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will be able to use PV + interneurons for therapeutic purposes.
Rett syndrome is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. However, neurons do not die, which suggests that this is not a neurodegenerative disorder. An important question for future therapeutic approaches to this and related disorders concerns phenotypic reversibility. Can viable but defective neurons be repaired, or is the damage done during development without normal MeCP2 irrevocable? Using a mouse model, we demonstrate robust phenotypic reversal, as activation of MeCP2 expression leads to striking loss of advanced neurological symptoms in both immature and mature adult animals.
SummarySharp wave-ripple (SWR) oscillations play a key role in memory consolidation during non-rapid eye movement sleep, immobility, and consummatory behavior. However, whether temporally modulated synaptic excitation or inhibition underlies the ripples is controversial. To address this question, we performed simultaneous recordings of excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) and local field potentials (LFPs) in the CA1 region of awake mice in vivo. During SWRs, inhibition dominated over excitation, with a peak conductance ratio of 4.1 ± 0.5. Furthermore, the amplitude of SWR-associated IPSCs was positively correlated with SWR magnitude, whereas that of EPSCs was not. Finally, phase analysis indicated that IPSCs were phase-locked to individual ripple cycles, whereas EPSCs were uniformly distributed in phase space. Optogenetic inhibition indicated that PV+ interneurons provided a major contribution to SWR-associated IPSCs. Thus, phasic inhibition, but not excitation, shapes SWR oscillations in the hippocampal CA1 region in vivo.
The hippocampus plays a key role in learning and memory. Previous studies suggested that the main types of principal neurons, dentate gyrus granule cells (GCs), CA3 pyramidal neurons, and CA1 pyramidal neurons, differ in their activity pattern, with sparse firing in GCs and more frequent firing in CA3 and CA1 pyramidal neurons. It has been assumed but never shown that such different activity may be caused by differential synaptic excitation. To test this hypothesis, we performed high‐resolution whole‐cell patch‐clamp recordings in anesthetized rats in vivo. In contrast to previous in vitro data, both CA3 and CA1 pyramidal neurons fired action potentials spontaneously, with a frequency of ∼3–6 Hz, whereas GCs were silent. Furthermore, both CA3 and CA1 cells primarily fired in bursts. To determine the underlying mechanisms, we quantitatively assessed the frequency of spontaneous excitatory synaptic input, the passive membrane properties, and the active membrane characteristics. Surprisingly, GCs showed comparable synaptic excitation to CA3 and CA1 cells and the highest ratio of excitation versus hyperpolarizing inhibition. Thus, differential synaptic excitation is not responsible for differences in firing. Moreover, the three types of hippocampal neurons markedly differed in their passive properties. While GCs showed the most negative membrane potential, CA3 pyramidal neurons had the highest input resistance and the slowest membrane time constant. The three types of neurons also differed in the active membrane characteristics. GCs showed the highest action potential threshold, but displayed the largest gain of the input‐output curves. In conclusion, our results reveal that differential firing of the three main types of hippocampal principal neurons in vivo is not primarily caused by differences in the characteristics of the synaptic input, but by the distinct properties of synaptic integration and input‐output transformation. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.
BACKGROUND AND PURPOSEProteinase-activated receptor-2 (PAR2) is widely expressed in the CNS under normal physiological conditions. However, its potential role in modulating neuronal excitability and synaptic transmission remains to be determined. Here, we have investigated whether PAR2 activation modulates synaptic activity in the hippocampus. EXPERIMENTAL APPROACHPAR2 activation and its effect on the hippocampus were examined in rat primary cultures and acute slices using whole cell patch clamp and standard extracellular recordings, respectively. KEY RESULTSPAR2 activation leads to a depolarization of hippocampal neurones and a paradoxical reduction in the occurrence of synaptically driven spontaneous action potentials (APs). PAR2-induced neuronal depolarization was abolished following either the inhibition of astrocytic function or antagonism of ionotropic glutamate receptors whilst the PAR2-induced decrease in AP frequency was also reduced when astrocytic function was inhibited. Furthermore, when examined in acute hippocampal slices, PAR2 activation induced a profound long-term depression of synaptic transmission that was dependent on NMDA receptor activation and was sensitive to disruption of astrocytic function. CONCLUSIONS AND IMPLICATIONSThese novel findings show that PAR2 activation indirectly inhibits hippocampal synaptic activity and indicate that these receptors may play an active role in modulating normal physiological CNS function, in addition to their role in pathophysiological disorders. Abbreviations(DL)-AP5, racemic (2R)-amino-5-phosphonovaleric acid; (S)-MCPG, (S)-a-methyl-4-carboxyphenylglycine; 2f
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