Hippocampal GABAergic Inhibitory Interneurons.

In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10-15% of the total neuronal population; however, their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and circuit function. Here we provide an overview of the current state of the field of interneuron research, focusing largely on the hippocampus. We discuss recent advances related to the various cell types, including their development and maturation, expression of subtype-specific voltage- and ligand-gated channels, and their roles in network oscillations. We also discuss recent technological advances and approaches that have permitted high-resolution, subtype-specific examination of their roles in numerous neural circuit disorders and the emerging therapeutic strategies to ameliorate such pathophysiological conditions. The ultimate goal of this review is not only to provide a touchstone for the current state of the field, but to help pave the way for future research by highlighting where gaps in our knowledge exist and how a complete appreciation of their roles will aid in future therapeutic strategies.

Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in AppNL-G-F/NL-G-F mice.

In the early stages of Alzheimer's disease (AD), the accumulation of the peptide amyloid-ß (Aß) damages synapses and disrupts neuronal activity, leading to the disruption of neuronal oscillations associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that are essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-F mouse model used in the present study. These mice appear to model the early stages of Aß-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-F mice, we analysed neuronal oscillations found in the hippocampus and medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the power of mPFC spindles and decrease in the power of hippocampal sharp-wave ripples was identified. The latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+ imaging, as well as a decrease in PV-expressing interneuron density. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.

Life Cycle Greenhouse Gas Emissions of the USPS Next-Generation Delivery Vehicle Fleet.

The United States Postal Service (USPS) plans to purchase 165,000 next-generation delivery vehicles (NGDVs) between 2023 and 2032. The USPS submitted an environmental impact statement (EIS) for two NGDV procurement scenarios: (1) 90% internal combustion engine vehicles (ICEVs) and 10% battery electric vehicles (BEVs) ("ICEV scenario") and (2) 100% BEVs ("BEV scenario"). To correct several significant deficiencies in the EIS, we conduct a cradle-to-grave life cycle greenhouse gas (GHG) assessment of these two scenarios. Our analysis improves upon the USPS's EIS by including vehicle production and end-of-life emissions, future grid decarbonization, and more accurate vehicle operating emissions. In our base case, we find that the ICEV and BEV scenarios would result in 15% greater and 8% fewer GHG emissions, respectively, than the USPS estimate. Favorable vehicle and grid development would result in 63% lower BEV scenario emissions than the USPS estimate. Consequently, we calculate a cumulative lifetime emission reduction of 57-82% (14.7-21.4 Mt CO2e) from procuring 100% BEVs instead of 10% BEVs, compared to the USPS's estimate of 10.3 Mt. Given the long NGDV lifetimes, committing to the ICEV scenario squanders an ideal use case for BEVs, jeopardizes meeting our climate goals, and forgoes potential climate and environmental justice co-benefits.

Charging Strategies to Minimize Greenhouse Gas Emissions of Electrified Delivery Vehicles.

Electrification of delivery fleets has emerged as an important opportunity to reduce the transportation sector's environmental impact, including reducing greenhouse gas (GHG) emissions. When, where, and how vehicles are charged, however, impact the reduction potential. Not only does the carbon intensity of the grid vary across time and space, but charging decisions also influence battery degradation rates, resulting in more or less frequent battery replacement. Here, we propose a model that accounts for the spatial and temporal differences in charging emissions using marginal emission factors and degradation-induced differences in production emissions using a semi-empirical degradation model. We analyze four different charging strategies and demonstrate that a baseline charging scenario, in which a vehicle is fully charged immediately upon returning to a central depot, results in the highest emissions and employing alternative charging methods can reduce emissions by 8-37%. We show that when, where, and how batteries are charged also impact the total cost of ownership. Although the lowest cost and the lowest emitting charging strategies often align, the lowest cost deployment location for electric delivery vehicles may not be in the same location that maximizes environmental benefits.

The Economic Merits of Flexible Carbon Capture and Sequestration as a Compliance Strategy with the Clean Power Plan.

Carbon capture and sequestration (CCS) may be a key technology for achieving large CO2 emission reductions. Relative to "normal" CCS, "flexible" CCS retrofits include solvent storage that allows the generator to temporarily reduce the CCS parasitic load and increase the generator's net efficiency, capacity, and ramp rate. Due to this flexibility, flexible CCS generators provide system benefits that normal CCS generators do not, which could make flexible CCS an economic CO2 emission reduction strategy. Here, we estimate the system-level cost effectiveness of reducing CO2 emissions with flexible CCS compared to redispatching (i.e., substituting gas- for coal-fired electricity generation), wind, and normal CCS under the Clean Power Plan (CPP) and a hypothetical more stringent CO2 emission reduction target ("stronger CPP"). Using a unit commitment and economic dispatch model, we find flexible CCS achieves more cost-effective emission reductions than normal CCS under both reduction targets, indicating that policies that promote CCS should encourage flexible CCS. However, flexible CCS is less cost effective than wind under both reduction targets and less and more cost effective than redispatching under the CPP and stronger CPP, respectively. Thus, CCS will likely be a minor CPP compliance strategy but may play a larger role under a stronger emission reduction target.

Fast gamma oscillations are generated intrinsically in CA1 without the involvement of fast-spiking basket cells.

Information processing in neuronal networks relies on the precise synchronization of ensembles of neurons, coordinated by the diverse family of inhibitory interneurons. Cortical interneurons can be usefully parsed by embryonic origin, with the vast majority arising from either the caudal or medial ganglionic eminences (CGE and MGE). Here, we examine the activity of hippocampal interneurons during gamma oscillations in mouse CA1, using an in vitro model where brief epochs of rhythmic activity were evoked by local application of kainate. We found that this CA1 KA-evoked gamma oscillation was faster than that in CA3 and, crucially, did not appear to require the involvement of fast-spiking basket cells. In contrast to CA3, we also found that optogenetic inhibition of pyramidal cells in CA1 did not significantly affect the power of the oscillation, suggesting that excitation may not be essential for gamma genesis in this region. We found that MGE-derived interneurons were generally more active than CGE interneurons during CA1 gamma, although a group of CGE-derived interneurons, putative trilaminar cells, were strongly phase-locked with gamma oscillations and, together with MGE-derived axo-axonic and bistratified cells, provide attractive candidates for being the driver of this locally generated, predominantly interneuron-driven model of gamma oscillations.

Navigating the circuitry of the brain's GPS system: Future challenges for neurophysiologists.

The discovery of the brain's navigation system creates a compelling challenge for neurophysiologists: how do we map the circuitry of a system that can only be definitively identified in awake, behaving animals? Do grid and border cells in the entorhinal cortex correspond to the two classes of principal cell found there, stellate and pyramidal cells? In the hippocampus, does the diversity seen in pyramidal cell subtypes have functional correlates in the place cell system? How do interneurons regulate the activity of spatially tuned principal cells in the hippocampal and entorhinal circuits? Here, we discuss recent literature relating the cellular circuitry of these circuits to in vivo studies of the brain's navigation system, and the role that interneurons have in regulating the activity of principal cells in these circuits. We propose that studying in vitro models of neuronal oscillations in the entorhinal cortex and hippocampus can provide useful insights for bridging the gap in understanding that exists in relating in vivo and behavioral studies to circuit function at the cellular level.

Mechanisms and implications of gamma oscillation plasticity.

A recent study by Hadler and colleagues uncovered a novel form of plasticity of gamma oscillations in an ex vivo hippocampal slice preparation which they term 'gamma potentiation'. We discuss the potential cellular mechanisms of this form of plasticity and its functional and translational implications.

Distinct roles of GABAB1a- and GABAB1b-containing GABAB receptors in spontaneous and evoked termination of persistent cortical activity.

During slow-wave sleep, cortical neurons display synchronous fluctuations between periods of persistent activity ('UP states') and periods of relative quiescence ('DOWN states'). Such UP and DOWN states are also seen in isolated cortical slices. Recently, we reported that both spontaneous and evoked termination of UP states in slices from the rat medial entorhinal cortex (mEC) involves GABA(B) receptors. Here, in order to dissociate the roles of GABA(B1a)- and GABA(B1b)-containing receptors in terminating UP states, we used mEC slices from mice in which either the GABA(B1a) or the GABA(B1b) subunit had been genetically ablated. Pharmacological blockade of GABA(B) receptors using the antagonist CGP55845 prolonged the UP state duration in both wild-type mice and those lacking the GABA(B1b) subunit, but not in those lacking the GABA(B1a) subunit. Conversely, electrical stimulation of layer 1 could terminate an ongoing UP state in both wild-type mice and those lacking the GABA(B1a) subunit, but not in those lacking the GABA(B1b) subunit. Together with previous reports, indicating a preferential presynaptic location of GABA(B1a)- and postsynaptic location of GABA(B1b)-containing receptors, these results suggest that presynaptic GABA(B) receptors contribute to spontaneous DOWN state transitions, whilst postsynaptic GABA(B) receptors are essential for the afferent termination of the UP state. Inputs to layer 1 from other brain regions could thus provide a powerful mechanism for synchronizing DOWN state transitions across cortical areas via activation of GABAergic interneurons targeting postsynaptic GABA(B) receptors.

Dopamine suppresses persistent network activity via D(1) -like dopamine receptors in rat medial entorhinal cortex.

Cortical networks display persistent activity in the form of periods of sustained synchronous depolarizations ('UP states') punctuated by periods of relative hyperpolarization ('DOWN states'), which together form the slow oscillation. UP states are known to be synaptically generated and are sustained by a dynamic balance of excitation and inhibition, with fast ionotropic glutamatergic excitatory and GABAergic inhibitory conductances increasing during the UP state. Previously, work from our group demonstrated that slow metabotropic GABA receptors also play an important role in terminating the UP state, but the effects of other neuromodulators on this network phenomenon have received little attention. Given that persistent activity is a neural correlate of working memory and that signalling through dopamine receptors has been shown to be critical for working memory tasks, we examined whether dopaminergic neurotransmission affected the slow oscillation. Here, using an in vitro model of the slow oscillation in rat medial entorhinal cortex, we showed that dopamine strongly and reversibly suppressed cortical UP states. We showed that this effect was mediated through D1 -like and not D2 -like dopamine receptors, and we found no evidence that tonic dopaminergic transmission affected UP states in our model.

Meteorological drivers of resource adequacy failures in current and high renewable Western U.S. power systems.

Power system resource adequacy (RA), or its ability to continually balance energy supply and demand, underpins human and economic health. How meteorology affects RA and RA failures, particularly with increasing penetrations of renewables, is poorly understood. We characterize large-scale circulation patterns that drive RA failures in the Western U.S. at increasing wind and solar penetrations by integrating power system and synoptic meteorology methods. At up to 60% renewable penetration and across analyzed weather years, three high pressure patterns drive nearly all RA failures. The highest pressure anomaly is the dominant driver, accounting for 20-100% of risk hours and 43-100% of cumulative risk at 60% renewable penetration. The three high pressure patterns exhibit positive surface temperature anomalies, mixed surface solar radiation anomalies, and negative wind speed anomalies across our region, which collectively increase demand and decrease supply. Our characterized meteorological drivers align with meteorology during the California 2020 rolling blackouts, indicating continued vulnerability of power systems to these impactful weather patterns as renewables grow.

No evidence from complementary data sources of a direct glutamatergic projection from the mouse anterior cingulate area to the hippocampal formation.

The connectivity and interplay between the prefrontal cortex and hippocampus underpin various key cognitive processes, with changes in these interactions being implicated in both neurodevelopmental and neurodegenerative conditions. Understanding the precise cellular connections through which this circuit is organised is, therefore, vital for understanding these same processes. Overturning earlier findings, a recent study described a novel excitatory projection from anterior cingulate area to dorsal hippocampus. We sought to validate this unexpected finding using multiple, complementary methods: anterograde and retrograde anatomical tracing, using anterograde and retrograde adeno-associated viral vectors, monosynaptic rabies tracing, and the Fast Blue classical tracer. Additionally, an extensive data search of the Allen Projection Brain Atlas database was conducted to find the stated projection within any of the deposited anatomical studies as an independent verification of our own results. However, we failed to find any evidence of a direct, monosynaptic glutamatergic projection from mouse anterior cingulate cortex to the hippocampus proper.

A cellular switchboard in memory circuits.

Neurogliaform cells can direct the flow of information through the hippocampus.

The costs of replacing coal plant jobs with local instead of distant wind and solar jobs across the United States.

To further a just energy transition, jobs lost at retiring coal plants could be replaced by jobs at wind and solar plants. No research quantifies the feasibility and costs of such an undertaking across the United States. Complicating such an undertaking are workers' place-based preferences that could prevent them from moving long distances, e.g. to high renewable resource regions. We formulate a bottom-up optimization model to quantify the technical feasibility and costs of replacing coal plant jobs with local versus distant jobs in the renewables sector. For the contiguous United States, we find replacing coal generation and employment with local wind and solar investments is feasible. Siting renewables local to instead of distant from retiring coal plants increases replacement costs by 5%-33% across sub-national regions and by $83 billion, or 24%, across the United States. These costs are modest relative to overall energy transition costs.

A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function.

Schizophrenia is a polygenetic disorder whose clinical onset is often associated with behavioral stress. Here, we present a model of disease pathogenesis that builds on our observation that the synaptic immediate early gene NPTX2 is reduced in cerebrospinal fluid of individuals with recent onset schizophrenia. NPTX2 plays an essential role in maintaining excitatory homeostasis by adaptively enhancing circuit inhibition. NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses and is coupled to circadian behavior. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. Modeling NPTX2 loss of function results in failure of parvalbumin interneurons in their adaptive contribution to behavioral stress, and animals exhibit multiple neuropsychiatric domains. Because the genetics of schizophrenia encompasses diverse proteins that contribute to excitatory synapse plasticity, the identified vulnerability of NPTX2 function can provide a framework for assessing the impact of genetics and the intersection with stress.

Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development.

In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. Although numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin 2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reveal how unique postsynaptic CAMs work in concert to control synaptogenesis and establish a general framework for GABAergic synapse development.

NPTX2 and cognitive dysfunction in Alzheimer's Disease.

Memory loss in Alzheimer's disease (AD) is attributed to pervasive weakening and loss of synapses. Here, we present findings supporting a special role for excitatory synapses connecting pyramidal neurons of the hippocampus and cortex with fast-spiking parvalbumin (PV) interneurons that control network excitability and rhythmicity. Excitatory synapses on PV interneurons are dependent on the AMPA receptor subunit GluA4, which is regulated by presynaptic expression of the synaptogenic immediate early gene NPTX2 by pyramidal neurons. In a mouse model of AD amyloidosis, Nptx2-/- results in reduced GluA4 expression, disrupted rhythmicity, and increased pyramidal neuron excitability. Postmortem human AD cortex shows profound reductions of NPTX2 and coordinate reductions of GluA4. NPTX2 in human CSF is reduced in subjects with AD and shows robust correlations with cognitive performance and hippocampal volume. These findings implicate failure of adaptive control of pyramidal neuron-PV circuits as a pathophysiological mechanism contributing to cognitive failure in AD.

Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons.

Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR(-/-) mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR(-/-) mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR(-/-) mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.

The emerging role of GABAB receptors as regulators of network dynamics: fast actions from a 'slow' receptor?

Convention holds that ionotropic receptors mediate fast neurotransmission and that 'slow' G-protein coupled metabotropic receptors have a secondary, modulatory role in the control of neuronal networks. Here, we discuss recent evidence showing that activation of metabotropic GABAB receptors in cortical layer 1 can powerfully inhibit principal cell activity and that their activation can rapidly halt ongoing network activity. Inputs from both within and without the cortex converge upon layer 1 where they target various populations of interneurons, including neurogliaform cells. We argue that neurogliaform cells are the main effector of a powerful inhibitory circuit that, acting through GABAB receptors, can be differentially recruited by long-range connections to serve in roles as diverse as conscious perception and memory consolidation.