Functional diversity of subicular principal cells during hippocampal ripples

Cortical and hippocampal oscillations play a crucial role in the encoding, consolidation, and retrieval of memory. Sharp-wave associated ripples have been shown to be necessary for the consolidation of memory. During consolidation, information is transferred from the hippocampus to the neocortex. One of the structures at the interface between hippocampus and neocortex is the subiculum. It is therefore well suited to mediate the transfer and distribution of information from the hippocampus to other areas. By juxtacellular and whole-cell-recordings in awake mice, we show here that in the subiculum a subset of pyramidal cells is activated, whereas another subset is inhibited during ripples. We demonstrate that these functionally different subgroups are predetermined by their cell subtype. Bursting cells are selectively used to transmit information during ripples, whereas the firing probability in regular firing cells is reduced. With multiple patch-clamp recordings in vitro, we show that the cell subtype-specific differences extend into the local network topology. This is reflected in an asymmetric wiring scheme where bursting cells and regular firing cells are recurrently connected among themselves but connections between subtypes exclusively exist from regular to bursting cells. Furthermore, inhibitory connections are more numerous onto regular firing cells than onto bursting cells. We conclude that the network topology contributes to the observed functional diversity of subicular pyramidal cells during sharp-wave associated ripples

Gamma-oscillation plasticity is mediated by parvalbumin interneurons

Understanding the plasticity of neuronal networks is an emerging field of (patho-)physiological research, yet little is known about the underlying cellular mechanisms. Gamma-oscillations (30 – 80 Hz), a biomarker of cognitive performance, require and potentiate glutamatergic transmission onto parvalbumin-positive interneurons (PVIs), suggesting an interface for cell-to-network plasticity. In ex vivo local field potential recordings, we demonstrate long-term potentiation of hippocampal gamma-power. Gamma-potentiation obeys established rules of PVI plasticity, requiring calcium-permeable AMPA receptors (CP-AMPARs) and metabotropic glutamate receptors (mGluRs). A microcircuit model of CA3 gamma-oscillations predicts CP-AMPAR plasticity onto PVIs critically outperforms pyramidal cell plasticity in increasing gamma-power and completely accounts for gamma-potentiation. We re-affirm this ex vivo in three PVI-targeting animal models, demonstrating that gamma-potentiation requires PVI-specific metabotropic signaling via a Gq/PKC-pathway comprising mGluR5 and a Gi-sensitive, PKA-dependent pathway. Gamma-activity dependent, metabotropically mediated CP-AMPAR plasticity on PVIs may serve as a guiding principle in understanding network plasticity in health and disease

Neuregulin 3 promotes excitatory synapse formation on hippocampal interneurons

Hippocampal GABAergic interneurons are crucial for cortical network function and have been implicated in psychiatric disorders. We show here that Neuregulin 3 (Nrg3), a relatively little investigated low-affinity ligand, is a functionally dominant interaction partner of ErbB4 in parvalbumin-positive (PV) interneurons. Nrg3 and ErbB4 are located pre- and postsynaptically, respectively, in excitatory synapses on PV interneurons in vivo. Additionally, we show that ablation of Nrg3 results in a similar phenotype as the one described for ErbB4 ablation, including reduced excitatory synapse numbers on PV interneurons, altered short-term plasticity, and disinhibition of the hippocampal network. In culture, presynaptic Nrg3 increases excitatory synapse numbers on ErbB4(+) interneurons and affects short-term plasticity. Nrg3 mutant neurons are poor donors of presynaptic terminals in the presence of competing neurons that produce recombinant Nrg3, and this bias requires postsynaptic ErbB4 but not ErbB4 kinase activity. Furthermore, when presented by non-neuronal cells, Nrg3 induces postsynaptic membrane specialization. Our data indicate that Nrg3 provides adhesive cues that facilitate excitatory neurons to synapse onto ErbB4(+) interneurons

Cellular and synaptic diversity of layer 2-3 pyramidal neurons in human individuals

Understanding the functional principles of the human brain requires deep insight into the neuronal and network physiology. To what extent such principles of cellular physiology and synaptic interactions are common across different human individuals is unknown. We characterized the physiology of ~1200 pyramidal neurons and ~1400 monosynaptic connections using advanced multineuron patch-clamp recordings in slices from human temporal cortex. To disentangle within and between individual sources of heterogeneity, we recorded up to 100 neurons per single subject. We found that neuronal, but not synaptic physiology varied with laminar depth. Connection probability was ~15% throughout layer 2-3. Synaptic amplitudes exhibited heavy-tailed distributions with an inverse power law relationship to short term plasticity. Neurons could be classified into four functional subtypes. These general principles of microcircuit physiology were common across individuals. Our study advances the understanding of human neuron and synaptic diversity from an individual and phenotypic perspective

The functional impact of LGI1 autoantibodies on human CA3 pyramidal neurons

Autoantibodies against leucine-rich glioma inactivated 1 protein (LGI1 mAb) lead to limbic encephalitis characterized by seizures and memory deficits. While animal models provide insights into mechanisms of LGI1 mAb action, species-specific confirmation is lacking. In this study, we investigated the effects of patient-derived LGI1 mAb on human CA3 neurons using cultured ex vivo slices. Analysis of intrinsic properties and morphology indicated functional integrity of these neurons under incubation conditions. Human CA3 neurons received spontaneous excitatory currents with large amplitudes and frequencies, suggestive of "giant" AMPA currents. In slices exposed to LGI1 mAb, human CA3 neurons displayed increased neuronal spike frequency, mirroring effects observed with the Kv1.1 channel blocker DTX-K. This increase likely resulted from decreased Kv1.1 channel activity at the axonal initial segment, as indicated by alterations in action potential properties. A detailed analysis revealed differences between LGI1 mAb and DTX-K effects on action potential properties, suggesting distinct mechanisms of action and emphasizing the need for further exploration of downstream pathways. Our findings underscore the importance of species specific confirmatory studies of disease mechanisms and highlight the potential of human hippocampal slice cultures as a translational model for investigation of disease mechanisms beyond epilepsy, including the effects of pharmacological compounds and autoantibodies

Routes to, from and within the subiculum

The subiculum is one of the major output areas of the hippocampus and has extensive projections to extrahippocampal targets. It is likely to play a pivotal role in the distribution of outgoing information from the hippocampus. The hippocampus, including the subiculum, is important for the formation, consolidation and retrieval of memory. These functions require a network that is flexible enough to encode incoming information and also allows for reliable distribution, storage and integration into previously encoded memories. Finally, relevant information has to be retrieved in a context-specific manner to allow for an appropriate behavioral response. The subiculum as a gateway between the hippocampus and cortex might serve to integrate and process information from the hippocampus proper and its other inputs before conveying it to more permanent storage locations. This review summarizes how the subiculum is embedded into upstream and downstream circuits, describes what is known about the local network topology and discusses cellular and functional properties of subicular cells subtypes. Lastly, it describes how these properties might help to separate information into parallel output streams and distribute it to its multiple target areas

Gamma oscillation plasticity is mediated via parvalbumin interneurons

Understanding the plasticity of neuronal networks is an emerging field of (patho-) physiological research, yet the underlying cellular mechanisms remain poorly understood. Gamma oscillations (30 to 80 hertz), a biomarker of cognitive performance, require and potentiate glutamatergic transmission onto parvalbumin-positive interneurons (PVIs), suggesting an interface for cell-to-network plasticity. In ex vivo local field potential recordings, we demonstrate long-term potentiation of hippocampal gamma power. Gamma potentiation obeys established rules of PVI plasticity, requiring calcium-permeable AMPA receptors (CP-AMPARs) and metabotropic glutamate receptors (mGluRs). A microcircuit computational model of CA3 gamma oscillations predicts CP-AMPAR plasticity onto PVIs critically outperforms pyramidal cell plasticity in increasing gamma power and completely accounts for gamma potentiation. We reaffirm this ex vivo in three PVI-targeting animal models, demonstrating that gamma potentiation requires PVI-specific signaling via a Gq/PKC pathway comprising mGluR5 and a Gi-sensitive, PKA-dependent pathway. Gamma activity-dependent, metabotropically mediated CP-AMPAR plasticity on PVIs may serve as a guiding principle in understanding network plasticity in health and disease

Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks

Networks of GABAergic interneurons are of critical importance for the generation of gamma frequency oscillations in the brain. To examine the underlying synaptic mechanisms, we made paired recordings from “basket cells” (BCs) in different subfields of hippocampal slices, using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the parvalbumin promoter. Unitary inhibitory postsynaptic currents (IPSCs) showed large amplitude and fast time course with mean amplitude-weighted decay time constants of 2.5, 1.2, and 1.8 ms in the dentate gyrus, and the cornu ammonis area 3 (CA3) and 1 (CA1), respectively (33–34°C). The decay of unitary IPSCs at BC–BC synapses was significantly faster than that at BC–principal cell synapses, indicating target cell-specific differences in IPSC kinetics. In addition, electrical coupling was found in a subset of BC–BC pairs. To examine whether an interneuron network with fast inhibitory synapses can act as a gamma frequency oscillator, we developed an interneuron network model based on experimentally determined properties. In comparison to previous interneuron network models, our model was able to generate oscillatory activity with higher coherence over a broad range of frequencies (20–110 Hz). In this model, high coherence and flexibility in frequency control emerge from the combination of synaptic properties, network structure, and electrical coupling

Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS

AbstractRecording of glutamate-activated currents in membrane patches was combined with RT-PCR-mediated AMPA receptor (AMPAR) subunit mRNA analysis in single identified cells of rat brain slices. Analysis of AMPARs in principal neurons and interneurons of hippocampus and neocortex and in auditory relay neurons and Bergmann glial cells indicates that the GluR-B subunit in its flip version determines formation of receptors with relatively slow gating, whereas the GluR-D subunit promotes assembly of more rapidly gated receptors. The relation between Ca2+ permeability of AMPAR channels and the relative GluR-B mRNA abundance is consistent with the dominance of this subunit in determining the Ca2+ permeability of native receptors. The results suggest that differential expression of GluR-B and GluR-D subunit genes, as well as splicing and editing of their mRNAs, account for the differences in gating and Ca2+ permeability of native AMPAR channels