Hippocampal sharp waves are population discharges initiated by an unknown mechanism in pyramidal cell networks of CA3. Axo-axonic cells (AACs) regulate action potential generation through GABAergic synapses on the axon initial segment. We found that CA3 AACs in anesthetized rats and AACs in freely moving rats stopped firing during sharp waves, when pyramidal cells fire most. AACs fired strongly and rhythmically around the peak of theta oscillations, when pyramidal cells fire at low probability. Distinguishing AACs from other parvalbumin-expressing interneurons by their lack of detectable SATB1 transcription factor immunoreactivity, we discovered a somatic GABAergic input originating from the medial septum that preferentially targets AACs. We recorded septo-hippocampal GABAergic cells that were activated during hippocampal sharp waves and projected to CA3. We hypothesize that inhibition of AACs, and the resulting subcellular redistribution of inhibition from the axon initial segment to other pyramidal cell domains, is a necessary condition for the emergence of sharp waves promoting memory consolidation.During slow wave sleep (SWS), quiet wakefulness and consummatory behavior, largeamplitude, 30-120-ms-duration 'sharp wave' voltage deflections have been observed in extracellular recordings throughout the mammalian hippocampal formation 1 , which occur simultaneously with 130-230 Hz 'ripples' most pronounced in stratum pyramidale (sPyr) of CA1 (refs. 2,3). These sharp wave-ripple complexes (SWRs) are required for memory © 2013 Nature America, Inc. All rights reserved.Reprints and permissions information is available online at http://www.nature.com/reprints/index.html.Correspondence should be addressed to T.J.V. (tim.viney@pharm.ox.ac.uk), B.L. (balint.lasztoczi@meduniwien.ac.at) or P.S. (peter.somogyi@pharm.ox.ac.uk). AUTHOR CONTRIBUTIONS T.J.V., B.L., L.K., M.G.C., J.J.T., T.K. and P.S. collected and analyzed data and wrote the paper. To expand on the equalcontributions footnote, each of the first four authors made important-though different-contributions, and hence they should be considered equal first authors.Note: Any Supplementary Information and Source Data files are available in the online version of the paper. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Neurosci. Author manuscript; available in PMC 2015 June 18. Published in final edited form as:Nat Neurosci. 2013 December ; 16(12): 1802-1811. doi:10.1038/nn.3550. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts consolidation 4 and have been postulated to originate from groups of pyramidal neurons in CA3 participating in a synchronous 'population burst', which is transmitted to the downstream CA1 region via Schaffer collaterals 5 . A proposed mechanism for SWR initiation is through disinhibition of pyramidal cells via dynamic state-dependent interactions between GABAergic neurons and glutamatergic inputs 1 . Indeed, in vivo recordings show ...
Medial septal GABAergic neurons of the basal forebrain innervate the hippocampus and related cortical areas, contributing to the coordination of network activity, such as theta oscillations and sharp wave-ripple events, via a preferential innervation of GABAergic interneurons. Individual medial septal neurons display diverse activity patterns, which may be related to their termination in different cortical areas and/or to the different types of innervated interneurons. To test these hypotheses, we extracellularly recorded and juxtacellularly labeled single medial septal neurons in anesthetized rats in vivo during hippocampal theta and ripple oscillations, traced their axons to distant cortical target areas, and analyzed their postsynaptic interneurons. Medial septal GABAergic neurons exhibiting different hippocampal theta phase preferences and/or sharp wave-ripple related activity terminated in restricted hippocampal regions, and selectively targeted a limited number of interneuron types, as established on the basis of molecular markers. We demonstrate the preferential innervation of bistratified cells in CA1 and of basket cells in CA3 by individual axons. One group of septal neurons was suppressed during sharp wave-ripples, maintained their firing rate across theta and non-theta network states and mainly fired along the descending phase of CA1 theta oscillations. In contrast, neurons that were active during sharp wave-ripples increased their firing significantly during “theta” compared to “non-theta” states, with most firing during the ascending phase of theta oscillations. These results demonstrate that specialized septal GABAergic neurons contribute to the coordination of network activity through parallel, target area- and cell type-selective projections to the hippocampus.
The 12 genome-wide association studies (GWAS) published to-date for late-onset Alzheimer’s disease (LOAD) have identified over 40 candidate LOAD risk modifiers, in addition to apolipoprotein (APOE) ε4. A few of these novel LOAD candidate genes, namely BIN1, CLU, CR1, EXOC3L2 and PICALM, have shown consistent replication, and are thus credible LOAD susceptibility genes. To evaluate other promising LOAD candidate genes, we have added data from our large, case–control series (n = 5,043) to meta-analyses of all published follow-up case–control association studies for six LOAD candidate genes that have shown significant association across multiple studies (TNK1, GAB2, LOC651924, GWA_14q32.13, PGBD1 and GALP) and for an additional nine previously suggested candidate genes. Meta-analyses remained significant at three loci after addition of our data: GAB2 (OR = 0.78, p = 0.007), LOC651924 (OR = 0.91, p = 0.01) and TNK1 (OR = 0.92, p = 0.02). Breslow–Day tests revealed significant heterogeneity between studies for GAB2 (p < 0.0001) and GWA_14q32.13 (p = 0.006). We have also provided suggestive evidence that PGBD1 (p = 0.04) and EBF3 (p = 0.03) are associated with age-at-onset of LOAD. Finally, we tested for interactions between these 15 genes, APOE ε4 and the five novel LOAD genes BIN1, CLU, CR1, EXOC3L2 and PICALM but none were significant after correction for multiple testing. Overall, this large, independent follow-up study for 15 of the top LOAD candidate genes provides support for GAB2 and LOC651924 (6q24.1) as risk modifiers of LOAD and novel associations between PGBD1 and EBF3 with age-at-onset.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-010-0924-2) contains supplementary material, which is available to authorized users.
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