Postdoctoral fellow, University of Birmingham at Alabama
Tonic and phasic activation of GIRKs contribute to mature low dentate granule cell excitability
The dentate gyrus (DG) is a main entry point for neural activity into the hippocampal formation, integrating sensory and spatial information from the cortex in a manner that generates a neural representation (“engram”) of a context. This role within the trisynaptic circuit requires that only a small fraction of the principal granule cells (GCs) are active at any given time. This sparse neural activity is enforced by powerful networks of inhibitory GABAergic interneurons in combination with low intrinsic excitability of GCs. Although the cellular and circuit properties that dictate synaptic inhibition are well studied, less is known about mechanisms that confer low GC intrinsic excitability. Using an electrophysiological approach here we demonstrate that intact G-protein mediated signaling is required to maintain the characteristic low resting membrane potential that differentiates dentate granule cells from CA1 pyramidal cells and immature adult born GCs. We show that intact G-protein signaling enables constitutive G-protein gated inwardly rectifying potassium channels (GIRK) activity, resulting in part from tonic GABAB receptor-mediated stimulation of GIRKs. Perforant path electric stimulation evokes a phasic activation of GIRKs by synaptic GABAB receptors on mature GCs, but adult born new GCs completely lack functional GIRK activity, with both tonic and phasic GABAB-receptor mediated GIRK signaling developing only after 3-4 weeks of maturation. Using transgenic mice and optogenetic tools we show that GABAB evoked phasic GIRK activation is interneuron specific, arising primarily from neuronal nitric oxide synthase (nNOS)-expressing interneurons rather than parvalbumin or somatostatin-expressing interneurons, and requires expression of GIRK2 subunits. Together these results demonstrate that G-protein mediated signaling robustly contributes to the low intrinsic excitability that differentiates mature and developing dentate GCs, and suggests that nNOS-expressing interneurons are principal gate-keepers of GABAB-receptor synaptic inhibition.
Abstract: Stress, a well-known sculptor of brain plasticity, is shown to suppress hippocampal neurogenesis in the adult brain; yet, the underlying cellular mechanisms are poorly investigated. Previous studies have shown that chronic stress triggers hyperphosphorylation and accumulation of the cytoskeletal protein Tau, a process that may impair the cytoskeleton-regulating role(s) of this protein with impact on neuronal function. Here, we analyzed the role of Tau on stress-driven suppression of neurogenesis in the adult dentate gyrus (DG) using animals lacking Tau (Tau-knockout; Tau-KO) and wild-type (WT) littermates. Unlike WTs, Tau-KO animals exposed to chronic stress did not exhibit reduction in DG proliferating cells, neuroblasts and newborn neurons; however, newborn astrocytes were similarly decreased in both Tau-KO and WT mice. In addition, chronic stress reduced phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/glycogen synthase kinase-3β (GSK3β)/β-catenin signaling, known to regulate cell survival and proliferation, in the DG of WT, but not Tau-KO, animals. These data establish Tau as a critical regulator of the cellular cascades underlying stress deficits on hippocampal neurogenesis in the adult brain.Molecular Psychiatry advance online publication, 30 May 2017; doi:10.1038/mp.2017.103.
Pub.: 31 May '17, Pinned: 16 Jun '17
Abstract: The generation of new neurons in the hippocampus of adult mammals has become a widely accepted phenomenon, but the functional significance of the adult neurogenesis in the hippocampus is not fully understood. One of the main hypotheses currently investigated suggests that neurogenesis contributes to pattern separation in the dentate gyrus. Many behavioral studies were conducted aiming to test this hypothesis using rodents as animal model. In those studies, researches ablated neurogenesis in the animals and subsequently evaluate them in tests of behavioral pattern separation, that is, behaviors that are thought to rely on the computational process of pattern separation. The results of these studies are varied, with most supporting a role for neurogenesis in pattern separation, but some others not. To address this controversy it was performed a systematic review and meta-analysis of studies evaluating the effect of neurogenesis ablation on behavioral pattern separation. Analysis results indicated that most of the literature in the topic is surprisingly consistent and, although there are two studies with divergent results, the bulk of the literature supports an effect of hippocampal neurogenesis on behavioral pattern separation. We discuss those findings in light of other behavioral effects of hippocampal neurogenesis ablation, limitations of behavioral data and other lines of evidence about the effect of hippocampal neurogenesis in the dentate gyrus. This article is protected by copyright. All rights reserved.
Pub.: 10 Jun '17, Pinned: 16 Jun '17
Abstract: It is well known that Notch1 signaling plays a crucial role in embryonic neural development and adult neurogenesis. The latest evidence shows that Notch1 also plays a critical role in synaptic plasticity in hippocampal mature neurons. So far, deeper insights into the function of Notch1 signaling during the different steps of adult neurogenesis are still lacking, and the mechanisms by which Notch1 dysfunction is associated with brain disorders are also poorly understood. In the current study, we found that Notch1 was highly expressed in the adult-born immature neurons in the hippocampal dentate gyrus. Using a genetic approach to selectively ablate Notch1 signaling in late immature precursors in the postnatal hippocampus by cross-breeding doublecortin (DCX)(+) neuron-specific proopiomelanocortin (POMC)-α Cre mice with floxed Notch1 mice, we demonstrated a previously unreported pivotal role of Notch1 signaling in survival and function of adult newborn neurons in the dentate gyrus. Moreover, behavioral and functional studies demonstrated that POMC-Notch1(-/-) mutant mice showed anxiety and depressive-like behavior with impaired synaptic transmission properties in the dentate gyrus. Finally, our mechanistic study showed significantly compromised phosphorylation of cAMP response element-binding protein (CREB) in Notch1 mutants, suggesting that the dysfunction of Notch1 mutants is associated with the disrupted pCREB signaling in postnatally generated immature neurons in the dentate gyrus.-Feng, S., Shi, T., Qiu, J., Yang, H., Wu, Y., Zhou, W., Wang, W., Wu, H. Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment.
Pub.: 15 Jun '17, Pinned: 16 Jun '17