Although brain-derived neurotrophic factor (BDNF) is known to regulate circuit development

Although brain-derived neurotrophic factor (BDNF) is known to regulate circuit development and synaptic plasticity, its exact role in neuronal network activity remains elusive. are a result of the synchronized electrical activity of the neurons within a network and are thought to be important for temporal encoding, binding of sensory features, and memory storage and retrieval (18C22). Moreover, gamma oscillations are altered in several brain disorders, such as Alzheimer’s disease (23C25), schizophrenia (24, 26C31), and epilepsy (24, 32, 33). Gamma oscillations are exquisitely susceptible to modulation of the cellular and synaptic mechanisms underlying the rhythmic activity. Fast-spiking PV+ interneurons are the main recipient of recurrent glutamatergic innervations in the hippocampal circuitry, and their part in gamma-frequency synchronization in cortical and hippocampal networks is definitely well-established (34, 35). Despite considerable knowledge of the part of BDNF-TrkB signaling in neuronal development and synaptic function, the query of how BDNF might modulate and control rhythmic activity offers so far not been solved. To determine whether BDNF regulates synchronized network activity through PV+ interneurons (36, 37), we used a mutant mouse collection, in which the gene has been selectively ablated in PV+ interneurons. By inducing gamma oscillations in the hippocampal slice preparation with the muscarinic acetylcholine receptor agonist carbamoylcholine (CCh), we found that the power of gamma oscillations was dramatically reduced in the hippocampal area CA1 of mutant mice RO4927350 compared with control (Ctr) littermates. Morphological analysis and concomitant whole-cell patch-clamp and extracellular field recordings were used to determine, whether the decrease in gamma oscillation power was caused by morphological and/or practical alterations in PV+ interneurons. We also showed that the removal of TrkB signaling prospects to a desynchronization and overall reduction in rate of recurrence of action potentials generated in PV+ interneurons, which is definitely consistent with a reduction in gamma oscillation power. Taken together, our results demonstrate a critical part of BDNF-TrkB signaling in PV+ interneurons for hippocampal network synchrony in the gamma-frequency band. Results Ablation of the Gene in PV+ Interneurons Using the PV-Cre Transgene. The calcium-binding protein PV serves as a marker of a subpopulation of GABAergic neurons with fast-spiking properties (38). To determine whether, and at what time point, PV+ interneurons communicate during hippocampal development, we performed PV immunohistochemical staining on sections from knockin mice, in which -galactosidase (-gal) recapitulates the manifestation pattern of (39). We found that the CA1 region starts to express before postnatal day time (P) 7 and PV between P7 and P14 (Fig. 1 and was indicated in nearly all PV+ interneurons (54 of 56) at P14 (Fig. 1B) and in all PV+ interneurons at P21 (Fig. 1during postnatal development and in adulthood. Fig. 1. Colocalization of TrkB and parvalbumin in the hippocampal CA1 region. Manifestation patterns of TrkB and parvalbumin in the hippocampal CA1 region were exposed by immunohistochemistry against parvalbumin and -galactosidase in mice at … We used a transgene driven from the PV promoter (gene in PV-expressing cells. To determine the effectiveness of RO4927350 gene deletion mediated by in PV+ interneurons, we launched this transgene into reporter (locus expresses -galactosidase once Cre-mediated recombination offers occurred (40). In mice, -gal was indicated in the majority (22 of 31) of PV+ interneurons in hippocampal area CA1. Importantly, the Cre recombination activity was purely limited to PV+ interneurons, because we did not detect any neurons that indicated -gal but not PV (Fig. 2allele recombination was recognized in the vast majority of PV+ neurons … We then crossed with floxed (knockout mice (gene was eliminated in PV+ interneurons of TrkB-PV?/? mice. First, a double-staining experiment was performed to detect TrkB mRNA by in situ hybridization (ISH) using fluorescence-labeled antisense oligonucleotides like a probe, and PV immunoreactivity by immunohistochemistry using an anti-PV antibody. We found that although many PV+ interneurons indicated TrkB mRNA in Ctr mice (Fig. 2ISH signals were detectable in PV-negative cells, suggesting the deletion of gene was selective for PV+ interneurons. For the second approach, laser capture microdissection (LCM) was used to capture PV+ interneurons in hippocampal sections, followed by quantitative reverse-transcriptase PCR (qPCR) to measure TrkB mRNA levels in the captured cells samples (Fig. 2< 0.05; Fig. 2gene in CA1 PV+ interneurons of TrkB-PV?/? mice. Interestingly, there was a 47.1 4.9% reduction in the level of mRNA in CA1 PV+ interneurons isolated from TrkB-PV?/? mice compared with those from Ctr mice (< 0.05; Fig. 2< 0.05) and by 19.2% at 6 wk of age (from 0.0285 to 0.023 cell per m3; < 0.01) (Fig. 3 RO4927350 and knockout (TrkB-PV?/?, or KO) and control RO4927350 (Ctr) mice. (< Fip3p 0.05) and a 19.8 4.9% reduction in SP (< 0.05) in TrkB-PV?/? mice, RO4927350 respectively, compared with Ctr mice (Fig. 3 and gene elicited a moderate effect on the dendrites and the number of PV+ interneurons in the hippocampal.

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