Associations Between Vitamin D Deficiency/Insufficiency and Depression Expose Health Disparities in Older Rural West Texans: A Project FRONTIER Study.

OBJECTIVE: To determine associations between Vitamin D (VD) levels and clinical depression through the Geriatric Depression Scale (GDS) and its questions and subdomains, stratified by demographics and Hispanic/Latino ethnicity (HLE). DESIGN, SETTING, AND PARTICIPANTS: A cohort of 299 Project FRONTIER participants aged 62.6 ± 11.7 years old, 70.9% female, and 40.5% HLE were used. Standard correlation and regression analyses were employed. MEASUREMENTS: The main outcome measures were VD (serum 25(OH)-VD) level, GDS-30 (30-item questionnaire), GDS-30 subfactors and questions, and HLE status. VD categories were defined as VD deficiency (VDD; ≤20 ng/mL), VD insufficiency (VDI; 21-29 ng/mL), VD sufficiency (30-38 ng/mL) and high VD sufficiency (>38 ng/mL). RESULTS: The majority (61.5%) of samples fell into VDD/VDI categories. A significant negative association was found between VD level and GDS-30 total score. VD level was negatively correlated with Dysphoria and Meaninglessness GDS-30 subfactors. Although GDS subfactors were similar between HLE and non-HLE groups, VD levels were significantly lower in HLE samples. Finally, HLE/non-HLE groups were differentially stratified across VD categories. Only 4% of HLEs fell into the high VD sufficient category, suggesting low VD supplementation. CONCLUSION: A significant negative association between VD level and depressive symptoms was revealed in our aging Project FRONTIER participants. HLE individuals were overrepresented in VDD/VDI samples, and VDD/VDI was associated primarily with the Dysphoria GDS subdomain. Regression analysis predicted high VD sufficiency (95.5 ng/mL) to be associated with no depressive symptoms (GDS=0). Our results underscore troubling disparities in VD-related depressive symptoms between HLE and non-HLE populations.

Cancer drugs with high repositioning potential for Alzheimer's disease.

INTRODUCTION: Despite the recent full FDA approval of lecanemab, there is currently no disease modifying therapy (DMT) that can efficiently slow down the progression of Alzheimer's disease (AD) in the general population. This statement emphasizes the need to identify novel DMTs in the shortest time possible to prevent a global epidemic of AD cases as the world population experiences an increase in lifespan. AREAS COVERED: Here, we review several classes of anti-cancer drugs that have been or are being investigated in Phase II/III clinical trials for AD, including immunomodulatory drugs, RXR agonists, sex hormone therapies, tyrosine kinase inhibitors, and monoclonal antibodies. EXPERT OPINION: Given the overall course of brain pathologies during the progression of AD, we express a great enthusiasm for the repositioning of anti-cancer drugs as possible AD DMTs. We anticipate an increasing number of combinatorial therapy strategies to tackle AD symptoms and their underlying pathologies. However, we strongly encourage improvements in clinical trial study designs to better assess target engagement and possible efficacy over sufficient periods of drug exposure.

The Contribution of Hippocampal All-Trans Retinoic Acid (ATRA) Deficiency to Alzheimer's Disease: A Narrative Overview of ATRA-Dependent Gene Expression in Post-Mortem Hippocampal Tissue.

There is accumulating evidence that vitamin A (VA) deficiency contributes to the pathogenesis and progression of Alzheimer's disease (AD). All-trans retinoic acid (ATRA), a metabolite of VA in the brain, serves distinct roles in the human hippocampus. Agonists of retinoic acid receptors (RAR), including ATRA, promote activation of the non-amyloidogenic pathway by enhancing expression of α-secretases, providing a mechanistic basis for delaying/preventing amyloid beta (Aß) toxicity. However, whether ATRA is actually deficient in the hippocampi of patients with AD is not clear. Here, using a publicly available human transcriptomic dataset, we evaluated the extent to which ATRA-sensitive genes are dysregulated in hippocampal tissue from post-mortem AD brains, relative to age-matched controls. Consistent with ATRA deficiency, we found significant dysregulation of many ATRA-sensitive genes and significant upregulation of RAR co-repressors, supporting the idea of transcriptional repression of ATRA-mediated signaling. Consistent with oxidative stress and neuroinflammation, Nrf2 and NfkB transcripts were upregulated, respectively. Interestingly, transcriptional targets of Nrf2 were not upregulated, accompanied by upregulation of several histone deacetylases. Overall, our investigation of ATRA-sensitive genes in the human hippocampus bolsters the scientific premise of ATRA depletion in AD and that epigenetic factors should be considered and addressed as part of VA supplementation.

RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease.

The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer's disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip+/- mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip+/- mice. Behavioral, basic motor and sensory function tests in Rlip+/- mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip+/- mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes.

Septohippocampal transmission from parvalbumin-positive neurons features rapid recovery from synaptic depression.

Parvalbumin-containing projection neurons of the medial-septum-diagonal band of Broca ([Formula: see text]) are essential for hippocampal rhythms and learning operations yet are poorly understood at cellular and synaptic levels. We combined electrophysiological, optogenetic, and modeling approaches to investigate [Formula: see text] neuronal properties. [Formula: see text] neurons had intrinsic membrane properties distinct from acetylcholine- and somatostatin-containing MS-DBB subtypes. Viral expression of the fast-kinetic channelrhodopsin ChETA-YFP elicited action potentials to brief (1-2 ms) 470 nm light pulses. To investigate [Formula: see text] transmission, light pulses at 5-50 Hz frequencies generated trains of inhibitory postsynaptic currents (IPSCs) in CA1 stratum oriens interneurons. Using a similar approach, optogenetic activation of local hippocampal PV ([Formula: see text]) neurons generated trains of [Formula: see text]-mediated IPSCs in CA1 pyramidal neurons. Both synapse types exhibited short-term depression (STD) of IPSCs. However, relative to [Formula: see text] synapses, [Formula: see text] synapses possessed lower initial release probability, transiently resisted STD at gamma (20-50 Hz) frequencies, and recovered more rapidly from synaptic depression. Experimentally-constrained mathematical synapse models explored mechanistic differences. Relative to the [Formula: see text] model, the [Formula: see text] model exhibited higher sensitivity to calcium accumulation, permitting a faster rate of calcium-dependent recovery from STD. In conclusion, resistance of [Formula: see text] synapses to STD during short gamma bursts enables robust long-range GABAergic transmission from MS-DBB to hippocampus.

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.

Current Status of Healthy Aging and Dementia Research: A Symposium Summary.

The purpose of the 'First Regional Healthy Aging and Dementia Research Symposium' was to discuss the latest research in healthy aging and dementia research, public health trends related to neurodegenerative diseases of aging, and community-based programs and research studying health, nutrition, and cognition. This symposium was organized by the Garrison Institute on Aging (GIA) of the Texas Tech University Health Sciences Center (TTUHSC), and was held in Lubbock, Texas, October 24-25, 2018. The Symposium joined experts from educational and research institutions across the United States. The two-day Symposium included all GIA staff and researchers. Students, postdoctoral fellows, and faculty members involved in dementia research presented at the Symposium. Healthcare professionals, from geriatricians to social workers working with patients with neurodegenerative diseases, also presented. In addition, experts traveled from across the United States to participate. This event was comprised of multiple sessions, each with several oral presentations, followed by questions and answers, and discussion.

M1 Muscarinic Receptors Modulate Fear-Related Inputs to the Prefrontal Cortex: Implications for Novel Treatments of Posttraumatic Stress Disorder.

BACKGROUND: The prefrontal cortex (PFC) integrates information from multiple inputs to exert top-down control allowing for appropriate responses in a given context. In psychiatric disorders such as posttraumatic stress disorder, PFC hyperactivity is associated with inappropriate fear in safe situations. We previously reported a form of muscarinic acetylcholine receptor (mAChR)-dependent long-term depression in the PFC that we hypothesize is involved in appropriate fear responding and could serve to reduce cortical hyperactivity following stress. However, it is unknown whether this long-term depression occurs at fear-related inputs. METHODS: Using optogenetics with extracellular and whole-cell electrophysiology, we assessed the effect of mAChR activation on the synaptic strength of specific PFC inputs. We used selective pharmacological tools to assess the involvement of M1 mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear-learning model. RESULTS: M1 mAChR activation induced long-term depression at inputs from the ventral hippocampus and basolateral amygdala but not from the mediodorsal nucleus of the thalamus. We found that systemic M1 mAChR antagonism impaired contextual fear extinction. Treatment with an M1 positive allosteric modulator enhanced contextual fear extinction consolidation in stress-enhanced fear learning-conditioned mice. CONCLUSIONS: M1 mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction, and M1 mAChR function is required for proper contextual fear extinction. Furthermore, an M1 positive allosteric modulator enhanced the consolidation of fear extinction in the stress-enhanced fear-learning model, suggesting that M1 positive allosteric modulators may provide a novel treatment strategy to facilitate exposure therapy in the clinic for the treatment of posttraumatic stress disorder.

Data Driven Models of Short-Term Synaptic Plasticity.

Simple models of short term synaptic plasticity that incorporate facilitation and/or depression have been created in abundance for different synapse types and circumstances. The analysis of these models has included computing mutual information between a stochastic input spike train and some sort of representation of the postsynaptic response. While this approach has proven useful in many contexts, for the purpose of determining the type of process underlying a stochastic output train, it ignores the ordering of the responses, leaving an important characterizing feature on the table. In this paper we use a broader class of information measures on output only, and specifically construct hidden Markov models (HMMs) (known as epsilon machines or causal state models) to differentiate between synapse type, and classify the complexity of the process. We find that the machines allow us to differentiate between processes in a way not possible by considering distributions alone. We are also able to understand these differences in terms of the dynamics of the model used to create the output response, bringing the analysis full circle. Hence this technique provides a complimentary description of the synaptic filtering process, and potentially expands the interpretation of future experimental results.

Effect of Neuromodulation of Short-term Plasticity on Information Processing in Hippocampal Interneuron Synapses.

Neurons in a micro-circuit connected by chemical synapses can have their connectivity affected by the prior activity of the cells. The number of synapses available for releasing neurotransmitter can be decreased by repetitive activation through depletion of readily releasable neurotransmitter (NT), or increased through facilitation, where the probability of release of NT is increased by prior activation. These competing effects can create a complicated and subtle range of time-dependent connectivity. Here we investigate the probabilistic properties of facilitation and depression (FD) for a presynaptic neuron that is receiving a Poisson spike train of input. We use a model of FD that is parameterized with experimental data from a hippocampal basket cell and pyramidal cell connection, for fixed frequency input spikes at frequencies in the range of theta (3-8 Hz) and gamma (20-100 Hz) oscillations. Hence our results will apply to micro-circuits in the hippocampus that are responsible for the interaction of theta and gamma rhythms associated with learning and memory. A control situation is compared with one in which a pharmaceutical neuromodulator (muscarine) is employed. We apply standard information-theoretic measures such as entropy and mutual information, and find a closed form approximate expression for the probability distribution of release probability. We also use techniques that measure the dependence of the response on the exact history of stimulation the synapse has received, which uncovers some unexpected differences between control and muscarine-added cases.

Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery.

Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination.

Ectopic transgene expression in the retina of four transgenic mouse lines.

Retinal expression of transgenes was examined in four mouse lines. Two constructs were driven by the choline acetyltransferase (ChAT) promoter: green fluorescent protein conjugated to tau protein (tau-GFP) or cytosolic yellow fluorescent protein (YFP) generated through CRE recombinase-induced expression of Rosa26 (ChAT-CRE/Rosa26YFP). Two other constructs targeted inhibitory interneurons: GABAergic horizontal and amacrine cells identified by glutamic acid decarboxylase (GAD65-GFP) or parvalbumin (PV) cells (PV-CRE/Rosa26YFP). Animals were transcardially perfused and retinal sections prepared. Antibodies against PV, calretinin (CALR), calbindin (CALB), and tyrosine hydroxylase (TH) were used to counterstain transgene-expressing cells. In PVxRosa and ChAT-tauGFP constructs, staining appeared in vertically oriented row of processes resembling Müller cells. In the ChATxRosa construct, populations of amacrine cells and neurons in the ganglion cell layer were labeled. Some cones also exhibited GFP fluorescence. CALR, PV and TH were found in none of these cells. Occasionally, we found GFP/CALR and GFP/PV double-stained cells in the ganglion cell layer (GCL). In the GAD65-GFP construct, all layers of the neuroretina were labeled, except photoreceptors. Not all horizontal cells expressed GFP. We did not find GFP/TH double-labeled cells and GFP was rarely present in CALR- and CALB-containing cells. Many PV-positive neurons were also labeled for GFP, including small diameter amacrines. In the GCL, single labeling for GFP and PV was ascertained, as well as several CALR/PV double-stained neurons. In the GCL, cells triple labeled with GFP/CALR/CALB were sparse. In conclusion, only one of the four transgenic constructs exhibited an expression pattern consistent with endogenous retinal protein expression, while the others strongly suggested ectopic gene expression.

Dendritic distributions of I h channels in experimentally-derived multi-compartment models of oriens-lacunosum/moleculare (O-LM) hippocampal interneurons.

The O-LM cell type mediates feedback inhibition onto hippocampal pyramidal cells and gates information flow in the CA1. Its functions depend on the presence of voltage-gated channels (VGCs), which affect its integrative properties and response to synaptic input. Given the challenges associated with determining densities and distributions of VGCs on interneuron dendrites, we take advantage of computational modeling to consider different possibilities. In this work, we focus on hyperpolarization-activated channels (h-channels) in O-LM cells. While h-channels are known to be present in O-LM cells, it is unknown whether they are present on their dendrites. In previous work, we used ensemble modeling techniques with experimental data to obtain insights into potentially important conductance balances. We found that the best O-LM models that included uniformly distributed h-channels in the dendrites could not fully capture the "sag" response. This led us to examine activation kinetics and non-uniform distributions of h-channels in the present work. In tuning our models, we found that different kinetics and non-uniform distributions could better reproduce experimental O-LM cell responses. In contrast to CA1 pyramidal cells where higher conductance densities of h-channels occur in more distal dendrites, decreasing conductance densities of h-channels away from the soma were observed in O-LM models. Via an illustrative scenario, we showed that having dendritic h-channels clearly speeds up back-propagating action potentials in O-LM cells, unlike when h-channels are present only in the soma. Although the present results were morphology-dependent, our work shows that it should be possible to determine the distributions and characteristics of O-LM cells with recordings and morphologies from the same cell. We hypothesize that h-channels are distributed in O-LM cell dendrites and endow them with particular synaptic integration properties that shape information flow in hippocampus.

Presynaptic cholinergic neuromodulation alters the temporal dynamics of short-term depression at parvalbumin-positive basket cell synapses from juvenile CA1 mouse hippocampus.

Parvalbumin-positive basket cells (PV BCs) of the CA1 hippocampus are active participants in theta (5-12 Hz) and gamma (20-80 Hz) oscillations in vivo. When PV BCs are driven at these frequencies in vitro, inhibitory postsynaptic currents (IPSCs) in synaptically connected CA1 pyramidal cells exhibit paired-pulse depression (PPD) and multiple-pulse depression (MPD). Moreover, PV BCs express presynaptic muscarinic acetylcholine receptors (mAChRs) that may be activated by synaptically released acetylcholine during learning behaviors in vivo. Using acute hippocampal slices from the CA1 hippocampus of juvenile PV-GFP mice, we performed whole cell recordings from synaptically connected PV BC-CA1 pyramidal cell pairs to investigate how bath application of 10 µM muscarine impacts PPD and MPD at CA1 PV BC-pyramidal cell synapses. In accordance with previous studies, PPD and MPD magnitude increased with stimulation frequency. mAChR activation reduced IPSC amplitude and transiently reduced PPD, but MPD was largely maintained. Consistent with a reduction in release probability (pr), MPD and mAChR activation increased both the coefficient of variation of IPSC amplitudes and the fraction of failures. Using variance-mean analysis, we converted MPD trains to pr functions and developed a kinetic model that optimally fit six distinct pr conditions. The model revealed that vesicular depletion caused MPD and that recovery from depression was dependent on calcium. mAChR activation reduced the presynaptic calcium transient fourfold and initial pr twofold, thereby reducing PPD. However, mAChR activation slowed calcium-dependent recovery from depression during sustained repetitive activity, thereby preserving MPD. Thus the activation of presynaptic mAChRs optimally protects PV BCs from vesicular depletion during short bursts of high-frequency activity.

Enteric plexuses of two choline-acetyltransferase transgenic mouse lines: chemical neuroanatomy of the fluorescent protein-expressing nerve cells.

We studied cholinergic circuit elements in the enteric nervous system (ENS) of two distinct transgenic mouse lines in which fluorescent protein expression was driven by the choline-acetyltransferase (ChAT) promoter. In the first mouse line, green fluorescent protein was fused to the tau gene. This construct allowed the visualization of the fiber tracts and ganglia, however the nerve cells were poorly resolved. In the second mouse line (ChATcre-YFP), CRE/loxP recombination yielded cytosolic expression of yellow fluorescent protein (YFP). In these preparations the morphology of enteric neurons could be well studied. We also determined the neurochemical identity of ENS neurons in muscular and submucous layers using antibodies against YFP, calretinin (CALR), calbindin (CALB), and vasoactive intestinal peptide (VIP). Confocal microscopic imaging was used to visualize fluorescently-conjugated secondary antibodies. In ChATcre-YFP preparations, YFP was readily apparent in somatodendritic regions of ENS neurons. In the myenteric plexus, YFP/CALR/VIP staining revealed that 34% of cholinergic cells co-labeled with CALR. Few single-stained CR-positive cells were observed. Neither YFP nor CALR co-localized with VIP. In GFP/CALB/CALR staining, all co-localization combinations were represented. In the submucosal plexus, YFP/CALR/VIP staining revealed discrete neuronal populations. However, in separate preparations, double labeling was observed for YFP/CALR and CALR/VIP. In YFP/CALR/CALB staining, all combinations of double staining and triple labeling were verified. In conclusion, the neurochemical coding of ENS neurons in these mouse lines is consistent with many observations in non-transgenic animals. Thus, they provide useful tools for physiological and pharmacological studies on distinct neurochemical subtypes of ENS neurons.

Measuring Aggregation of Events about a Mass Using Spatial Point Pattern Methods.

We present a methodology that detects event aggregation about a mass surface using 3-dimensional study regions with a point pattern and a mass present. The Aggregation about a Mass function determines aggregation, randomness, or repulsion of events with respect to the mass surface. Our method closely resembles Ripley's K function but is modified to discern the pattern about the mass surface. We briefly state the definition and derivation of Ripley's K function and explain how the Aggregation about a Mass function is different. We develop the novel function according to the definition: the Aggregation about a Mass function times the intensity is the expected number of events within a distance h of a mass. Special consideration of edge effects is taken in order to make the function invariant to the location of the mass within the study region. Significance of aggregation or repulsion is determined using simulation envelopes. A simulation study is performed to inform researchers how the Aggregation about a Mass function performs under different types of aggregation. Finally, we apply the Aggregation about a Mass function to neuroscience as a novel analysis tool by examining the spatial pattern of neurotransmitter release sites as events about a neuron.

Muscarinic excitation of parvalbumin-positive interneurons contributes to the severity of pilocarpine-induced seizures.

OBJECTIVE: A common rodent model in epilepsy research employs the muscarinic acetylcholine receptor (mAChR) agonist pilocarpine, yet the mechanisms underlying the induction of pilocarpine-induced seizures (PISs) remain unclear. Global M1 mAChR (M1 R) knockout mice are resistant to PISs, implying that M1 R activation disrupts excitation/inhibition balance. Parvalbumin-positive (PV) inhibitory neurons express M1 Rs, participate in cholinergically induced oscillations, and can enter a state of depolarization block (DB) during epileptiform activity. Here, we test the hypothesis that pilocarpine activation of M1 Rs expressed on PV cells contributes to PISs. METHODS: CA1 PV cells in PV-CRE mice were visualized with a floxed YFP or hM3Dq-mCherry adeno-associated virus, or by crossing PV-CRE mice with the RosaYFP reporter line. To eliminate M1 Rs from PV cells, we generated PV-M1 knockout (KO) mice by crossing PV-CRE and floxed M1 mice. Action potential (AP) frequency was monitored during application of pilocarpine (200 µm). In behavioral experiments, locomotion and seizure symptoms were recorded in wild-type (WT) or PV-M1 KO mice during PISs. RESULTS: Pilocarpine significantly increased AP frequency in CA1 PV cells into the gamma range. In the continued presence of pilocarpine, a subset (5/7) of PV cells progressed to DB, which was mimicked by hM3Dq activation of Gq-receptor signaling. Pilocarpine-induced depolarization, AP firing at gamma frequency, and progression to DB were prevented in CA1 PV cells of PV-M1 KO mice. Finally, compared to WT mice, PV-M1 KO mice were associated with reduced severity of PISs. SIGNIFICANCE: Pilocarpine can directly depolarize PV+ cells via M1 R activation, but a subset of these cells progress to DB. Our electrophysiologic and behavioral results suggest that this mechanism is active during PISs, contributing to a collapse of PV-mediated γ-aminobutyric acid (GABA)ergic inhibition, dysregulation of excitation/inhibition balance, and increased susceptibility to PISs.

A kinetic model for the frequency dependence of cholinergic modulation at hippocampal GABAergic synapses.

In this paper we use a simple model of presynaptic neuromodulation of GABA signaling to decipher paired whole-cell recordings of frequency dependent cholinergic neuromodulation at CA1 parvalbumin-containing basket cell (PV BC)-pyramidal cell synapses. Variance-mean analysis is employed to normalize the data, which is then used to estimate parameters in the mathematical model. Various parameterizations and hidden parameter dependencies are investigated using Markov Chain Monte Carlo (MCMC) parameter estimation techniques. This analysis reveals that frequency dependence of cholinergic modulation requires both calcium-dependent recovery from depression and mAChR-induced inhibition of presynaptic calcium entry. A reduction in calcium entry into the presynaptic terminal in the kinetic model accounted for the frequency-dependent effects of mAChR activation.

Using multi-compartment ensemble modeling as an investigative tool of spatially distributed biophysical balances: application to hippocampal oriens-lacunosum/moleculare (O-LM) cells.

Multi-compartmental models of neurons provide insight into the complex, integrative properties of dendrites. Because it is not feasible to experimentally determine the exact density and kinetics of each channel type in every neuronal compartment, an essential goal in developing models is to help characterize these properties. To address biological variability inherent in a given neuronal type, there has been a shift away from using hand-tuned models towards using ensembles or populations of models. In collectively capturing a neuron's output, ensemble modeling approaches uncover important conductance balances that control neuronal dynamics. However, conductances are never entirely known for a given neuron class in terms of its types, densities, kinetics and distributions. Thus, any multi-compartment model will always be incomplete. In this work, our main goal is to use ensemble modeling as an investigative tool of a neuron's biophysical balances, where the cycling between experiment and model is a design criterion from the start. We consider oriens-lacunosum/moleculare (O-LM) interneurons, a prominent interneuron subtype that plays an essential gating role of information flow in hippocampus. O-LM cells express the hyperpolarization-activated current (Ih). Although dendritic Ih could have a major influence on the integrative properties of O-LM cells, the compartmental distribution of Ih on O-LM dendrites is not known. Using a high-performance computing cluster, we generated a database of models that included those with or without dendritic Ih. A range of conductance values for nine different conductance types were used, and different morphologies explored. Models were quantified and ranked based on minimal error compared to a dataset of O-LM cell electrophysiological properties. Co-regulatory balances between conductances were revealed, two of which were dependent on the presence of dendritic Ih. These findings inform future experiments that differentiate between somatic and dendritic Ih, thereby continuing a cycle between model and experiment.

Direct excitation of parvalbumin-positive interneurons by M1 muscarinic acetylcholine receptors: roles in cellular excitability, inhibitory transmission and cognition.

Parvalbumin-containing (PV) neurons, a major class of GABAergic interneurons, are essential circuit elements of learning networks. As levels of acetylcholine rise during active learning tasks, PV neurons become increasingly engaged in network dynamics. Conversely, impairment of either cholinergic or PV interneuron function induces learning deficits. Here, we examined PV interneurons in hippocampus (HC) and prefrontal cortex (PFC) and their modulation by muscarinic acetylcholine receptors (mAChRs). HC PV cells, visualized by crossing PV-CRE mice with Rosa26YFP mice, were anatomically identified as basket cells and PV bistratified cells in the stratum pyramidale; in stratum oriens, HC PV cells were electrophysiologically distinct from somatostatin-containing cells. With glutamatergic transmission pharmacologically blocked, mAChR activation enhanced PV cell excitability in both CA1 HC and PFC; however, CA1 HC PV cells exhibited a stronger postsynaptic depolarization than PFC PV cells. To delete M1 mAChRs genetically from PV interneurons, we created PV-M1 knockout mice by crossing PV-CRE and floxed M1 mice. The elimination of M1 mAChRs from PV cells diminished M1 mAChR immunoreactivity and muscarinic excitation of HC PV cells. Selective cholinergic activation of HC PV interneurons using Designer Receptors Exclusively Activated by Designer Drugs technology enhanced the frequency and amplitude of inhibitory synaptic currents in CA1 pyramidal cells. Finally, relative to wild-type controls, PV-M1 knockout mice exhibited impaired novel object recognition and, to a lesser extent, impaired spatial working memory, but reference memory remained intact. Therefore, the direct activation of M1 mAChRs on PV cells contributes to some forms of learning and memory.