Oriens-lacunosum Moleculare Cells Research Articles

Synaptic and dendritic architecture of different types of hippocampal somatostatin interneurons.

GABAergic inhibitory neurons fundamentally shape the activity and plasticity of cortical circuits. A major subset of these neurons contains somatostatin (SOM); these cells play crucial roles in neuroplasticity, learning, and memory in many brain areas including the hippocampus, and are implicated in several neuropsychiatric diseases and neurodegenerative disorders. Two main types of SOM-containing cells in area CA1 of the hippocampus are oriens-lacunosum-moleculare (OLM) cells and hippocampo-septal (HS) cells. These cell types show many similarities in their soma-dendritic architecture, but they have different axonal targets, display different activity patterns in vivo, and are thought to have distinct network functions. However, a complete understanding of the functional roles of these interneurons requires a precise description of their intrinsic computational properties and their synaptic interactions. In the current study we generated, analyzed, and make available several key data sets that enable a quantitative comparison of various anatomical and physiological properties of OLM and HS cells in mouse. The data set includes detailed scanning electron microscopy (SEM)-based 3D reconstructions of OLM and HS cells along with their excitatory and inhibitory synaptic inputs. Combining this core data set with other anatomical data, patch-clamp electrophysiology, and compartmental modeling, we examined the precise morphological structure, inputs, outputs, and basic physiological properties of these cells. Our results highlight key differences between OLM and HS cells, particularly regarding the density and distribution of their synaptic inputs and mitochondria. For example, we estimated that an OLM cell receives about 8,400, whereas an HS cell about 15,600 synaptic inputs, about 16% of which are GABAergic. Our data and models provide insight into the possible basis of the different functionality of OLM and HS cell types and supply essential information for more detailed functional models of these neurons and the hippocampal network.

Lack of Hyperinhibition of Oriens Lacunosum-Moleculare Cells by Vasoactive Intestinal Peptide-Expressing Cells in a Model of Temporal Lobe Epilepsy.

Temporal lobe epilepsy remains a common disorder with no cure and inadequate treatments, potentially because of an incomplete understanding of how seizures start. CA1 pyramidal cells and many inhibitory interneurons increase their firing rate in the seconds-minutes before a spontaneous seizure in epileptic rats. However, some interneurons fail to do so, including those identified as putative interneurons with somata in oriens and axons targeting lacunosum-moleculare (OLM cells). Somatostatin-containing cells, including OLM cells, are the primary target of inhibitory vasoactive intestinal polypeptide and calretinin-expressing (VIP/CR) bipolar interneuron-selective interneurons, type 3 (ISI-3). The objective of this study was to test the hypothesis that in epilepsy inhibition of OLM cells by ISI-3 is abnormally increased, potentially explaining the failure of OLM recruitment when needed most during the ramp up of activity preceding a seizure. Stereological quantification of VIP/CR cells in a model of temporal lobe epilepsy demonstrated that they survive in epileptic mice, despite a reduction in their somatostatin-expressing (Som) cell targets. Paired recordings of unitary IPSCs (uIPSCs) from ISI-3 to OLM cells did not show increased connection probability or increased connection strength, and failure rate was unchanged. When miniature postsynaptic currents in ISI-3 were compared, only mIPSC frequency was increased in epileptic hippocampi. Nevertheless, spontaneous and miniature postsynaptic potentials were unchanged in OLM cells of epileptic mice. These results are not consistent with the hypothesis of hyperinhibition from VIP/CR bipolar cells impeding recruitment of OLM cells in advance of a seizure.

Integration of Within-Cell Experimental Data With Multi-Compartmental Modeling Predicts H-Channel Densities and Distributions in Hippocampal OLM Cells.

Determining biophysical details of spatially extended neurons is a challenge that needs to be overcome if we are to understand the dynamics of brain function from cellular perspectives. Moreover, we now know that we should not average across recordings from many cells of a given cell type to obtain quantitative measures such as conductance since measures can vary multiple-fold for a given cell type. In this work we examine whether a tight combination of experimental and computational work can address this challenge. The oriens-lacunosum/moleculare (OLM) interneuron operates as a “gate” that controls incoming sensory and ongoing contextual information in the CA1 of the hippocampus, making it essential to understand how its biophysical properties contribute to memory function. OLM cells fire phase-locked to the prominent hippocampal theta rhythms, and we previously used computational models to show that OLM cells exhibit high or low theta spiking resonance frequencies that depend respectively on whether their dendrites have hyperpolarization-activated cation channels (h-channels) or not. However, whether OLM cells actually possess dendritic h-channels is unknown at present. We performed a set of whole-cell recordings of OLM cells from mouse hippocampus and constructed three multi-compartment models using morphological and electrophysiological parameters extracted from the same OLM cell, including per-cell pharmacologically isolated h-channel currents. We found that the models best matched experiments when h-channels were present in the dendrites of each of the three model cells created. This strongly suggests that h-channels must be present in OLM cell dendrites and are not localized to their somata. Importantly, this work shows that a tight integration of model and experiment can help tackle the challenge of characterizing biophysical details and distributions in spatially extended neurons. Full spiking models were built for two of the OLM cells, matching their current clamp cell-specific electrophysiological recordings. Overall, our work presents a technical advancement in modeling OLM cells. Our models are available to the community to use to gain insight into cellular dynamics underlying hippocampal function.

Computationally going where experiments cannot: a dynamical assessment of dendritic ion channel currents during in vivo-like states

Background: Despite technological advances, how specific cell types are involved in brain function remains shrouded in mystery. Further, little is known about the contribution of different ion channel currents to cell excitability across different neuronal subtypes and their dendritic compartments in vivo. The picture that we do have is largely based on somatic recordings performed in vitro. Uncovering dendritic ion channel current contributions in neuron subtypes that represent a minority of the neuronal population is not currently a feasible task using purely experimental means. Methods: We employ two morphologically-detailed multi-compartment models of a specific type of inhibitory interneuron, the oriens lacunosum moleculare (OLM) cell. The OLM cell is a well-studied cell type in CA1 hippocampus that is important in gating sensory and contextual information. We create in vivo-like states for these cellular models by including levels of synaptic bombardment that would occur in vivo. Using visualization tools and analyses we assess the ion channel current contribution profile across the different somatic and dendritic compartments of the models. Results: We identify changes in dendritic excitability, ion channel current contributions and co-activation patterns between in vitro and in vivo-like states. Primarily, we find that the relative timing between ion channel currents are mostly invariant between states, but exhibit changes in magnitudes and decreased propagation across dendritic compartments. We also find enhanced dendritic hyperpolarization-activated cyclic nucleotide-gated channel (h-channel) activation during in vivo-like states, which suggests that dendritically located h-channels are functionally important in altering signal propagation in the behaving animal. Conclusions: Overall, we have demonstrated, using computational modelling, the dynamical changes that can occur to ion channel mechanisms governing neuronal spiking. Simultaneous access to dendritic compartments during simulated in vivo states shows that the magnitudes of some ion channel current contributions are differentially altered during in vivo-like states relative to in vitro.

Computationally going where experiments cannot: a dynamical assessment of dendritic ion channel currents during in vivo-like states

Background: Despite technological advances, how specific cell types are involved in brain function remains shrouded in mystery. Further, little is known about the contribution of different ion channel currents to cell excitability across different neuronal subtypes and their dendritic compartments in vivo. The picture that we do have is largely based on somatic recordings performed in vitro. Uncovering dendritic ion channel current contributions in neuron subtypes that represent a minority of the neuronal population is not currently a feasible task using purely experimental means. Methods: We employ two morphologically-detailed multi-compartment models of a specific type of inhibitory interneuron, the oriens lacunosum moleculare (OLM) cell. The OLM cell is a well-studied cell type in CA1 hippocampus that is important in gating sensory and contextual information. We create in vivo-like states for these cellular models by including levels of synaptic bombardment that would occur in vivo. Using visualization tools and analyses we assess the ion channel current contribution profile across the different somatic and dendritic compartments of the models. Results: We identify changes in dendritic excitability, ion channel current contributions and co-activation patterns between in vitro and in vivo-like states. Primarily, we find that the relative timing between ion channel currents are mostly invariant between states, but exhibit changes in magnitudes and decreased propagation across dendritic compartments. We also find enhanced dendritic hyperpolarization-activated cyclic nucleotide-gated channel (h-channel) activation during in vivo-like states, which suggests that dendritically located h-channels are functionally important in altering signal propagation in the behaving animal. Conclusions: Overall, we have demonstrated, using computational modelling, the dynamical changes that can occur to ion channel mechanisms governing neuronal spiking. Simultaneous access to dendritic compartments during simulated in vivo states shows that the magnitudes of some ion channel current contributions are differentially altered during in vivo-like states relative to in vitro.

Computationally going where experiments cannot: a dynamical assessment of dendritic ion channel currents during in vivo-like states.

Background: Despite technological advances, how specific cell types are involved in brain function remains shrouded in mystery. Further, little is known about the contribution of different ion channel currents to cell excitability across different neuronal subtypes and their dendritic compartments in vivo. The picture that we do have is largely based on somatic recordings performed in vitro. Uncovering dendritic ion channel current contributions in neuron subtypes that represent a minority of the neuronal population is not currently a feasible task using purely experimental means. Methods: We employ two morphologically-detailed multi-compartment models of a specific type of inhibitory interneuron, the oriens lacunosum moleculare (OLM) cell. The OLM cell is a well-studied cell type in CA1 hippocampus that is important in gating sensory and contextual information. We create in vivo-like states for these cellular models by including levels of synaptic bombardment that would occur in vivo. Using visualization tools and analyses we assess the ion channel current contribution profile across the different somatic and dendritic compartments of the models. Results: We identify changes in dendritic excitability, ion channel current contributions and co-activation patterns between in vitro and in vivo-like states. Primarily, we find that the relative timing between ion channel currents are mostly invariant between states, but exhibit changes in magnitudes and decreased propagation across dendritic compartments. We also find enhanced dendritic hyperpolarization-activated cyclic nucleotide-gated channel (h-channel) activation during in vivo-like states, which suggests that dendritically located h-channels are functionally important in altering signal propagation in the behaving animal. Conclusions: Overall, we have demonstrated, using computational modelling, the dynamical changes that can occur to ion channel mechanisms governing neuronal spiking in vitro and in vivo. In particular, we have shown that the magnitudes of some ion channel current contributions are differentially altered during in vivo-like states relative to in vitro.

Synergy of Glutamatergic and Cholinergic Modulation Induces Plateau Potentials in Hippocampal OLM Interneurons.

Oriens-lacunosum moleculare (OLM) cells are hippocampal inhibitory interneurons that are implicated in the regulation of information flow in the CA1 circuit, inhibiting cortical inputs to distal pyramidal cell dendrites, whilst disinhibiting CA3 inputs to pyramidal cells. OLM cells express metabotropic cholinergic (mAChR) and glutamatergic (mGluR) receptors, so modulation of these cells via these receptors may contribute to switching between functional modes of the hippocampus. Using a transgenic mouse line to identify OLM cells, we found that both mAChR and mGluR activation caused the cells to exhibit long-lasting depolarizing plateau potentials following evoked spike trains. Both mAChR- and mGluR-induced plateau potentials were eliminated by blocking transient receptor potential (TRP) channels, and were dependent on intracellular calcium concentration and calcium entry. Pharmacological tests indicated that Group I mGluRs are responsible for the glutamatergic induction of plateaus. There was also a pronounced synergy between the cholinergic and glutamatergic modulation, plateau potentials being generated by agonists applied together at concentrations too low to elicit any change when applied individually. This synergy could enable OLM cells to function as coincidence detectors of different neuromodulatory systems, leading to their enhanced and prolonged activation and a functional change in information flow within the hippocampus.

Single-cell RNA-Seq characterization of anatomically identified OLM interneurons in different transgenic mouse lines.

Inhibitory GABAergic interneurons create different brain activity patterns that correlate with behavioural states. In this characterizing study, we used single‐cell RNA‐Seq to analyse anatomically‐ and electrophysiologically identified hippocampal oriens‐lacunosum moleculare (OLM) interneurons. OLMs express somatostatin (Sst), generate feedback inhibition and play important roles in theta oscillations and fear encoding. Although an anatomically‐ and biophysically homogenous population, OLMs presumably comprise of two functionally distinct types with different developmental origins, inferred from the expression pattern of serotonin type‐3a (5‐HT3a, or Htr3a) receptor subunit and 5‐HT excitability in a set of OLMs. To broadly characterize OLM cells, we used the Sst‐Cre and the BAC transgenic Htr3a‐Cre mouse lines and separately analysed SstCre‐OLM and Htr3aCre‐OLM types. We found a surprisingly consistent expression of Npy in OLMs, which was previously not associated with the identity of this type. Our analyses furthermore revealed uniform expression of developmental origin‐related genes, including transcription factors and neurexin isoforms, without providing support for the current view that OLMs may originate from multiple neurogenic zones. Together, we found that OLMs constitute a highly homogenous transcriptomic population. Finally, our results revealed surprisingly infrequent expression of Htr3a in only ~10% of OLMs and an apparently specific expression of the 5‐HT3b subunit‐coding gene Htr3b in Htr3aCre‐OLMs, but not in SstCre‐OLMs. However, additional in situ hybridization experiments suggested that the differential expression of Htr3b may represent an unexpected consequence arising from the design of the Htr3a‐Cre BAC transgenic line.

Chrna2-OLM interneurons display different membrane properties and h-current magnitude depending on dorsoventral location.

The hippocampus is an extended structure displaying heterogeneous anatomical cell layers along its dorsoventral axis. It is known that dorsal and ventral regions show different integrity when it comes to functionality, innervation, gene expression, and pyramidal cell properties. Still, whether hippocampal interneurons exhibit different properties along the dorsoventral axis is not known. Here, we report electrophysiological properties of dorsal and ventral oriens lacunosum moleculare (OLM) cells from coronal sections of the Chrna2-cre mouse line. We found dorsal OLM cells to exhibit a significantly more depolarized resting membrane potential compared to ventral OLM cells, while action potential properties were similar between the two groups. We found ventral OLM cells to show a higher initial firing frequency in response to depolarizing current injections but also to exhibit a higher spike-frequency adaptation than dorsal OLM cells. Additionally, dorsal OLM cells displayed large membrane sags in response to negative current injections correlating with our results showing that dorsal OLM cells have more hyperpolarization-activated current (Ih ) compared to ventral OLM cells. Immunohistochemical examination indicates the h-current to correspond to hyperpolarization-activated cyclic nucleotide-gated subunit 2 (HCN2) channels. Computational studies suggest that Ih in OLM cells is essential for theta oscillations in hippocampal circuits, and here we found dorsal OLM cells to present a higher membrane resonance frequency than ventral OLM cells. Thus, our results highlight regional differences in membrane properties between dorsal and ventral OLM cells allowing this interneuron to differently participate in the generation of hippocampal theta rhythms depending on spatial location along the dorsoventral axis of the hippocampus.

Phase relations of theta oscillations in a computer model of the hippocampal CA1 field: Key role of Schaffer collaterals

The hippocampal theta rhythm (4–12 Hz) is one of the most important electrophysiological processes in the hippocampus, it participates in cognitive hippocampal functions, such as navigation in space, novelty detection, and declarative memory. We use neural network modeling to study the mechanism of theta rhythm emergence in the CA1 microcircuitry. Our model of the CA1 field includes biophysical representation of major cell types related to the theta rhythm emergence: excitatory pyramidal cells and two types of inhibitory interneurons, PV+ basket cells and oriens lacunosum–moleculare (OLM) cells. The main inputs to the CA1 cells come from the entorhinal cortex via perforant pathway, the CA3 field via Schaffer collaterals, and the medial septum via fimbria–fornix. By computer simulations we investigated the influence of each input, intrinsic parameters of neurons, and connections between neurons on phase coupling between the theta rhythm and the firing of pyramidal, PV+ basket and OLM cells in the CA1. We found that the input from the CA3 field via Schaffercollaterals plays a major role in the formation of phase relations that have been observed in experiments in vivo. The direct input from the medial septum participates in the formation of proper phase relations, but it is not crucial for the production of the theta rhythm in CA1 neural populations.

Ventral hippocampal OLM cells control type 2 theta oscillations and response to predator odor

Dorsal and ventral hippocampus regions exert cognition and emotion-related functions, respectively. Since both regions display rhythmic activity, specific neural oscillatory pacemakers may underlie their functional dichotomy. Type 1 theta oscillations are independent of cholinergic transmission and are observed in the dorsal hippocampus during movement and exploration. In contrast, type 2 theta depends on acetylcholine and appears when animals are exposed to emotionally laden contexts such as a predator presence. Despite its involvement in emotions, type 2 theta has not been associated with the ventral hippocampus. Here, we show that optogenetic activation of oriens-lacunosum moleculare (OLM) interneurons in the ventral hippocampus drives type 2 theta. Moreover, we found that type 2 theta generation is associated with increased risk-taking behavior in response to predator odor. These results demonstrate that two theta oscillations subtypes originate in the two hippocampal regions that predominantly underlie either cognitive or emotion-related functions.

Deciphering the Contribution of Oriens-Lacunosum/Moleculare (OLM) Cells to Intrinsic θ Rhythms Using Biophysical Local Field Potential (LFP) Models.

Oscillations in local field potentials (LFPs) are prevalent and contribute to brain function. An understanding of the cellular correlates and pathways affecting LFPs is needed, but many overlapping pathways in vivo make this difficult to achieve. A prevalent LFP rhythm in the hippocampus associated with memory processing and spatial navigation is the θ (3–12 Hz) oscillation. θ rhythms emerge intrinsically in an in vitro whole hippocampus preparation and this reduced preparation makes it possible to assess the contribution of different cell types to LFP generation. We focus on oriens-lacunosum/moleculare (OLM) cells as a major class of interneurons in the hippocampus. OLM cells can influence pyramidal (PYR) cells through two distinct pathways: by direct inhibition of PYR cell distal dendrites, and by indirect disinhibition of PYR cell proximal dendrites. We use previous inhibitory network models and build biophysical LFP models using volume conductor theory. We examine the effect of OLM cells to ongoing intrinsic LFP θ rhythms by directly comparing our model LFP features with experiment. We find that OLM cell inputs regulate the robustness of LFP responses without affecting their average power and that this robust response depends on coactivation of distal inhibition and basal excitation. We use our models to estimate the spatial extent of the region generating LFP θ rhythms, leading us to predict that about 22,000 PYR cells participate in intrinsic θ generation. Besides obtaining an understanding of OLM cell contributions to intrinsic LFP θ rhythms, our work can help decipher cellular correlates of in vivo LFPs.

Target-specific alterations in the VIP inhibitory drive to hippocampal GABAergic cells after status epilepticus

Status epilepticus (SE) is associated with complex reorganization of hippocampal circuits involving a significant loss of specific subtypes of GABAergic interneurons. While adaptive circuit plasticity may increase the chances for recruitment of surviving interneurons, the underlying mechanisms remain largely unknown. We studied the alterations in the inhibitory tone received by the hippocampal CA1 oriens/alveus (O/A) interneurons from the vasoactive intestinal peptide (VIP)- and calretinin (CR)-expressing interneurons using the pilocarpine-induced status epilepticus (SE) model of epilepsy. Our data showed that, while the overall density of the VIP/CR-co-expressing interneurons remained preserved, the number of axonal boutons made by these cells within the CA1 O/A was significantly lower after SE. Furthermore, VIP/CR interneurons exhibited significant alterations in their dendritic morphology and passive membrane properties. Subsequently, while all O/A interneuron types, including oriens-lacunosum moleculare (OLM), bistratified (Bis) and basket cells, exhibited decrease in spontaneous inhibitory drive, Bis and basket cells showed a smaller amplitude of light-evoked IPSCs mediated by the selective activation of VIP-positive interneurons. These data point to the target cell-specific changes in the inhibitory tone provided by the VIP cells to O/A interneurons following SE. Given that basket, Bis and OLM cells coordinate different subcellular domains of pyramidal neurons, significant disinhibition of basket and Bis cells along with a previously reported loss of the OLMs may result in a redistribution of inhibition converging onto pyramidal neurons, with a direct impact onto their recruitment to epileptiform network activity and seizure propagation.

Molecular heterogeneity of aggrecan-based perineuronal nets around five subclasses of parvalbumin-expressing neurons in the mouse hippocampus.

Subsets of GABAergic neurons are surrounded by perineuronal nets (PNNs), which play a critical role in the regulation of neural plasticity and neuroprotection. Although the plant lectin Wisteria floribunda agglutinin (WFA) has been commonly used to label PNNs, WFA only detects N-acetyl-d-galactosamine on aggrecan, a member of the lectican family. In this study, we used WFA and the antibody against the core protein of aggrecan (ACAN) to investigate the molecular heterogeneity of aggrecan-based PNNs around five subclasses of parvalbumin-expressing (PV+) γ-aminobutyric acid (GABA)ergic neurons in the CA1 and CA3 regions of the mouse hippocampus. The vast majority of ACAN+ PNNs were colocalized with WFA in the stratum pyramidale, whereas a substantial population of ACAN+ PNNs lacked WFA labeling in the stratum oriens. We then defined the subclasses of PV+ neurons based on their cellular locations, molecular expression, and septal projection. Like the WFA+ PNNs, ACAN+ PNNs surrounded PV+ basket cells and bistratified cells but not axo-axonic cells. Unlike the WFA+ PNNs, ACAN+ PNNs frequently surrounded PV+ oriens-lacunosum moleculare cells and hippocampo-septal cells. Interestingly, the relative densities of GABAergic synapses were higher around PV+ neurons with ACAN+ PNNs than around those without ACAN+ PNNs. Degradation of WFA+ PNNs by chondroitinase ABC did not affect the GABAergic synaptic densities around PV+ neurons. Our findings suggest that the molecular composition of aggrecan-based PNNs around PV+ neurons may differ in a subclass-specific manner, and also might help determine the functional involvement of PNNs in the regulation of GABAergic synapses around PV+ neurons in the hippocampus. J. Comp. Neurol. 525:1234-1249, 2017. © 2016 Wiley Periodicals, Inc.

Impaired function of α2-containing nicotinic acetylcholine receptors on oriens-lacunosum moleculare cells causes hippocampus-dependent memory impairments

Children of mothers who smoked during pregnancy are at significantly greater risk for cognitive impairments including memory deficits, but the mechanisms underlying this effect remain to be understood. In rodent models of smoking during pregnancy, early postnatal nicotine exposure results in impaired long-term hippocampus-dependent memory, functional loss of α2-containing nicotinic acetylcholine receptors (α2∗ nAChRs) in oriens-lacunosum moleculare (OLM) cells, increased CA1 network excitation, and unexpected facilitation of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses. Here we demonstrate that α2 knockout mice show the same pattern of memory impairment as previously observed in wild-type mice exposed to early postnatal nicotine. However, α2 knockout mice and α2 knockout mice exposed to early postnatal nicotine did not share all of the anomalies in hippocampal function observed in wild-type mice treated with nicotine during development. Unlike nicotine-treated wild-type mice, α2 knockout mice and nicotine-exposed α2 knockout mice did not demonstrate increased CA1 network excitation following Schaffer collateral stimulation and facilitated LTP, indicating that the effects are likely adaptive changes caused by activation of α2∗ nAChRs during nicotine exposure and are unlikely related to the associated memory impairment. Thus, the functional loss of α2∗ nAChRs in OLM cells likely plays a critical role in mediating this developmental-nicotine-induced hippocampal memory deficit.

Multiple mechanisms of theta rhythm generation in a model of the hippocampus

Hippocampal theta oscillations (4-12 Hz) are consistently recorded during memory tasks and spatial navigation. While computational models suggested specific mechanisms for theta generation, experimental inactivation of these mechanisms did not disrupt theta, precluding definitive conclusions about their roles. We investigated this discrepancy using a biophysical model of the hippocampus that included several of the components implicated in rhythm generation, all constrained by prior experimental results. The CA3 network model included recurrently connected pyramidal cells, and inhibitory basket cells (BC) and oriens-lacunosum moleculare (OLM) cells. The model was developed by matching experimental results characterizing neuronal firing patterns, synaptic dynamics, short-term synaptic plasticity and the three-dimensional organization of the hippocampus. The model revealed four mechanisms that generated theta oscillations: intrinsic theta resonance of pyramidal cells, recurrent connections between them, coupling between OLM and pyramidal cells, and, as a novel finding, the correlated input from entorhinal cortex. Consistent with experimental results, inactivation of any single mechanism did not disrupt the rhythm. Another novel finding was that the low and high cholinergic states differentially recruited theta generating mechanisms. Atropine -sensitive and -resistant forms of theta, however, corresponded to theta generated during low and high levels of network excitation, respectively. These findings provided an alternative interpretation of the atropine-based classification of theta oscillations, and suggested that the theta rhythm is an intrinsic property of the network. Any experimental manipulation or brain state that enhances or suppresses excitation might also, therefore, non-specifically enhance or suppress theta oscillations.

Early postnatal nicotine exposure disrupts the α2* nicotinic acetylcholine receptor-mediated control of oriens-lacunosum moleculare cells during adolescence in rats

Maternal cigarette smoking during pregnancy and maternal nicotine exposure in animal models are associated with cognitive impairments in offspring. However, the underlying mechanism remains unknown. Oriens-lacunosum moleculare (OLM) cells expressing α2* nicotinic acetylcholine receptors (nAChRs) are an important component of hippocampal circuitry, gating information flow and long-term potentiation (LTP) in the CA1 region. Here we investigated whether early postnatal nicotine exposure alters the normal role of α2*-nAChR-expressing OLM cells during adolescence in rats. We found that early postnatal nicotine exposure significantly decreased not only the number of α2-mRNA-expressing interneurons in the stratum oriens/alveus, but also α2*-nAChR-mediated responses in OLM cells. These effects of nicotine were prevented by co-administration with the nonselective nAChR antagonist mecamylamine, suggesting that nicotine-induced activation, but not desensitization, of nAChRs mediates the effects. α2*-nAChR-mediated depolarization of OLM cells normally triggers action potentials, causing an increase in spontaneous inhibitory postsynaptic currents in synaptically connected pyramidal cells. However, these α2*-nAChR-mediated effects were profoundly reduced after early postnatal nicotine exposure, suggesting altered control of CA1 circuits by α2*-nAChR-expressing OLM cells. Furthermore, these effects were associated with altered excitatory neural activity and LTP as well as the loss of normal α2*-nAChR-mediated control of excitatory neural activity and LTP. These findings suggest the altered function of α2*-nAChR-expressing OLM cells as an important target of further study for identifying the mechanisms underlying the cognitive impairment induced by maternal smoking during pregnancy.

Network models provide insights into how oriens-lacunosum-moleculare and bistratified cell interactions influence the power of local hippocampal CA1 theta oscillations.

Hippocampal theta is a 4–12 Hz rhythm associated with episodic memory, and although it has been studied extensively, the cellular mechanisms underlying its generation are unclear. The complex interactions between different interneuron types, such as those between oriens–lacunosum-moleculare (OLM) interneurons and bistratified cells (BiCs), make their contribution to network rhythms difficult to determine experimentally. We created network models that are tied to experimental work at both cellular and network levels to explore how these interneuron interactions affect the power of local oscillations. Our cellular models were constrained with properties from patch clamp recordings in the CA1 region of an intact hippocampus preparation in vitro. Our network models are composed of three different types of interneurons: parvalbumin-positive (PV+) basket and axo-axonic cells (BC/AACs), PV+ BiCs, and somatostatin-positive OLM cells. Also included is a spatially extended pyramidal cell model to allow for a simplified local field potential representation, as well as experimentally-constrained, theta frequency synaptic inputs to the interneurons. The network size, connectivity, and synaptic properties were constrained with experimental data. To determine how the interactions between OLM cells and BiCs could affect local theta power, we explored how the number of OLM-BiC connections and connection strength affected local theta power. We found that our models operate in regimes that could be distinguished by whether OLM cells minimally or strongly affected the power of network theta oscillations due to balances that, respectively, allow compensatory effects or not. Inactivation of OLM cells could result in no change or even an increase in theta power. We predict that the dis-inhibitory effect of OLM cells to BiCs to pyramidal cell interactions plays a critical role in the resulting power of network theta oscillations. Overall, our network models reveal a dynamic interplay between different classes of interneurons in influencing local theta power.

Unit Activity of Hippocampal Interneurons before Spontaneous Seizures in an Animal Model of Temporal Lobe Epilepsy.

Mechanisms of seizure initiation are unclear. To evaluate the possible roles of inhibitory neurons, unit recordings were obtained in the dentate gyrus, CA3, CA1, and subiculum of epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Most interneurons in the dentate gyrus, CA1, and subiculum increased their firing rate before seizures, and did so with significant consistency from seizure to seizure. Identification of CA1 interneuron subtypes based on firing characteristics during theta and sharp waves suggested that a parvalbumin-positive basket cell and putative bistratified cells, but not oriens lacunosum moleculare cells, were activated preictally. Preictal changes occurred much earlier than those described by most previous in vitro studies. Preictal activation of interneurons began earliest (>4 min before seizure onset), increased most, was most prevalent in the subiculum, and was minimal in CA3. Preictal inactivation of interneurons was most common in CA1 (27% of interneurons) and included a putative ivy cell and parvalbumin-positive basket cell. Increased or decreased preictal activity correlated with whether interneurons fired faster or slower, respectively, during theta activity. Theta waves were more likely to occur before seizure onset, and increased preictal firing of subicular interneurons correlated with theta activity. Preictal changes by other hippocampal interneurons were largely independent of theta waves. Within seconds of seizure onset, many interneurons displayed a brief pause in firing and a later, longer drop that was associated with reduced action potential amplitude. These findings suggest that many interneurons inactivate during seizures, most increase their activity preictally, but some fail to do so at the critical time before seizure onset.

A computational study on how theta modulated inhibition can account for the long temporal windows in the entorhinal–hippocampal loop

A recent experimental study (Mizuseki, Sirota, Pastalkova, & Buzsaki, 2009) has shown that the temporal delays between population activities in successive entorhinal and hippocampal anatomical stages are longer (about 70–80ms) than expected from axon conduction velocities and passive synaptic integration of feed-forward excitatory inputs. We investigate via computer simulations the mechanisms that give rise to such long temporal delays in the hippocampus structures. A model of the dentate gyrus (DG), CA3 and CA1 microcircuits is presented that uses biophysical representations of the major cell types including granule cells, CA3 and CA1 pyramidal cells (PCs) and six types of interneurons: basket cells (BCs), axo-axonic cells (AACs), bistratified cells (BSCs), oriens lacunosum-moleculare cells (OLMs), mossy cells (MCs) and hilar perforant path associated cells (HC). Inputs to the network came from the entorhinal cortex (EC) (layers 2 and 3) and the medial septum (MS). The model simulates accurately the timing of firing of different hippocampal cells with respect to the theta rhythm. The model shows that the experimentally reported long temporal delays in the DG, CA3 and CA1 hippocampal regions are due to theta modulated somatic and axonic inhibition. The model further predicts that the phase at which the CA1 PCs fire with respect to the theta rhythm is determined primarily by their increased dendritic excitability caused by the decrease of the axial resistance and the A-type K+ conductance along their dendritic trunk. The model predicted latencies by which the DG, CA3 and CA1 principal cells fire are inline with the experimental evidence. Finally, the model proposes functional roles for the different inhibitory interneurons in the retrieval of the memory pattern by the DG, CA3 and CA1 networks. The model makes a number of predictions, which can be tested experimentally, thus leading to a better understanding of the biophysical computations in the hippocampus.