GABAergic Circuits Research Articles

Frequency-dependent centrifugal modulation of the activity of different classes of mitral and tufted cells in olfactory bulb.

Mitral/tufted cells (M/TCs), the principal output neuron classes form complex circuits with bulbar neurons and long-range centrifugal circuits with higher processing areas such as the horizontal limb of the diagonal band of Broca (HDB). The precise excitability of output neurons is sculpted by local inhibitory circuits. Here, light-gated cation channel channelrhodopsin-2 (ChR2) was expressed in HDB GABAergic neurons to investigate the short-term plasticity of evoked postsynaptic currents/potentials of HDB input to all classes of M/TCs and effects on firing in the acute slice preparation. Activation of the HDB directly inhibited all classes of output neurons exhibiting frequency-dependent short-term depression of evoked inhibitory postsynaptic current (eIPSC)/potential (eIPSP), resulting in decreased inhibition of responses to olfactory nerve input as a function of input frequency. In contrast, activation of an indirect circuit of HDB→interneurons→M/TCs induced frequency-dependent disinhibition, resulting in short-term facilitation of evoked excitatory postsynaptic current (eEPSC) eliciting a burst or cluster of spiking in M/TCs. The facilitatory effects of elevated HDB input frequency were strongest on deeper output neurons (deep tufted and mitral cells) and negligible on peripheral output neurons (external and superficial tufted cells). Taken together, GABAergic HDB activation generates frequency-dependent regulation that differentially affects the excitability and responses across the five classes of M/TCs. This regulation may help maintain the precise balance between inhibition and excitation of neuronal circuits across the populations of output neurons in the face of changes in an animal sniffing rate, putatively to enhance and sharpen the tuning specificity of individual or classes of M/TCs to odors.NEW & NOTEWORTHY Neuronal circuits in the olfactory bulb closely modulate olfactory bulb output activity. Activation of GABAergic circuits from the HDB to the olfactory bulb has both direct and indirect action differentially across the five classes of M/TC bulbar output neurons. The net effect enhances the excitability of deeper output neurons as HDB frequency increases, altering the relative inhibition-excitation balance of output circuits. We hypothesize that this sharpens the tuning specificity of classes of M/TCs to odors during sensory processing.

Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus

The hypothalamic suprachiasmatic nucleus (SCN) is the master mammalian circadian clock. Its cell-autonomous timing mechanism, a transcriptional/translational feedback loop (TTFL), drives daily peaks of neuronal electrical activity, which in turn control circadian behavior. Intercellular signals, mediated by neuropeptides, synchronize and amplify TTFL and electrical rhythms across the circuit. SCN neurons are GABAergic, but the role of GABA in circuit-level timekeeping is unclear. How can a GABAergic circuit sustain circadian cycles of electrical activity, when such increased neuronal firing should become inhibitory to the network? To explore this paradox, we show that SCN slices expressing the GABA sensor iGABASnFR demonstrate a circadian oscillation of extracellular GABA ([GABA]e) that, counterintuitively, runs in antiphase to neuronal activity, with a prolonged peak in circadian night and a pronounced trough in circadian day. Resolving this unexpected relationship, we found that [GABA]e is regulated by GABA transporters (GATs), with uptake peaking during circadian day, hence the daytime trough and nighttime peak. This uptake is mediated by the astrocytically expressed transporter GAT3 (Slc6a11), expression of which is circadian-regulated, being elevated in daytime. Clearance of [GABA]e in circadian day facilitates neuronal firing and is necessary for circadian release of the neuropeptide vasoactive intestinal peptide, a critical regulator of TTFL and circuit-level rhythmicity. Finally, we show that genetic complementation of the astrocytic TTFL alone, in otherwise clockless SCN, is sufficient to drive [GABA]e rhythms and control network timekeeping. Thus, astrocytic clocks maintain the SCN circadian clockwork by temporally controlling GABAergic inhibition of SCN neurons.

The effects of transcutaneous auricular vagal nerve stimulation on cortical GABA-ergic and cholinergic circuits: a transcranial magnetic stimulation study.

Neurophysiological evidence that transcutaneous auricular vagal nerve stimulation (taVNS) affects neuronal signaling at the cortical level is sparse. We used transcranial magnetic stimulation to assess the effect of taVNS on the excitability of intracortical GABA-ergic and cholinergic circuits. In this within-subject, double-blind study on 30 healthy participants, we used TMS paradigms to assess the effect of a single session of taVNS at 100Hz and sham earlobe VNS (sVNS) on short-interval intracortical inhibition (SICI) curve and short-latency afferent inhibition (SAI). Control experiment was performed on additional 15 participants using the same experimental settings, but delivering no stimulation (xVNS). Bayesian statistics were used to assess the differences, producing % values that reflect the certainty that the values of interest were decreased during or after stimulation compared to baseline. taVNS increased SICI (96.3%), whereas sVNS decreased SICI (1.2 %). SAI was not affected by taVNS, while it was decreased during sVNS (1.34% and 9.1 %, for interstimulus intervals 20 and 24ms, respectively). The changes in TMS parameters detected during sVNS were present in the same direction in the control experiment with no stimulation. Our study provides evidence that taVNS increases the activity of cortical GABA-A-ergic system, leaving cortical cholinergic circuits unaffected. Changes in intracortical cortical excitability during sVNS, which were also observed in the control experiment with no stimulation were likely the effect of expectation related to participation in an interventional study.

Acan downregulation in parvalbumin GABAergic cells reduces spontaneous recovery of fear memories.

While persistence of fear memories is essential for survival, a failure to inhibit fear in response to harmless stimuli is a feature of anxiety disorders. Extinction training only temporarily suppresses fear memory recovery in adults, but it is highly effective in juvenile rodents. Maturation of GABAergic circuits, in particular of parvalbumin-positive (PV+) cells, restricts plasticity in the adult brain, thus reducing PV+ cell maturation could promote the suppression of fear memories following extinction training in adults. Epigenetic modifications such as histone acetylation control gene accessibility for transcription and help couple synaptic activity to changes in gene expression. Histone deacetylase 2 (Hdac2), in particular, restrains both structural and functional synaptic plasticity. However, whether and how Hdac2 controls the maturation of postnatal PV+ cells is not well understood. Here, we show that PV+- cell specific Hdac2 deletion limits spontaneous fear memory recovery in adult mice, while enhancing PV+ cell bouton remodeling and reducing perineuronal net aggregation around PV+ cells in prefrontal cortex and basolateral amygdala. Prefrontal cortex PV+ cells lacking Hdac2, show reduced expression of Acan, a critical perineuronal net component, which is rescued by Hdac2 re-expression. Pharmacological inhibition of Hdac2 before extinction training is sufficient to reduce both spontaneous fear memory recovery and Acan expression in wild-type adult mice, while these effects are occluded in PV+-cell specific Hdac2 conditional knockout mice. Finally, a brief knock-down of Acan expression mediated by intravenous siRNA delivery before extinction training but after fear memory acquisition is sufficient to reduce spontaneous fear recovery in wild-type mice. Altogether, these data suggest that controlled manipulation of PV+ cells by targeting Hdac2 activity, or the expression of its downstream effector Acan, promotes the long-term efficacy of extinction training in adults.

Amygdala circuit transitions supporting developmentally-appropriate social behavior

Social behaviors dynamically change throughout the lifespan alongside the maturation of neural circuits. The basolateral region of the amygdala (BLA), in particular, undergoes substantial maturational changes from birth throughout adolescence that are characterized by changes in excitation, inhibition, and dopaminergic modulation. In this review, we detail the trajectory through which BLA circuits mature and are influenced by dopaminergic systems to guide transitions in social behavior in infancy and adolescence using data from rodents. In early life, social behavior is oriented towards approaching the attachment figure, with minimal BLA involvement. Around weaning age, dopaminergic innervation of the BLA introduces avoidance of novel peers into rat pups’ behavioral repertoire. In adolescence, social behavior transitions towards peer-peer interactions with a high incidence of social play-related behaviors. This transition coincides with an increasing role of the BLA in the regulation of social behavior. Adolescent BLA maturation can be characterized by an increasing integration and function of local inhibitory GABAergic circuits and their engagement by the medial prefrontal cortex (mPFC). Manipulation of these transitions using viral circuit dissection techniques and early adversity paradigms reveals the sensitivity of this system and its role in producing age-appropriate social behavior.

Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer’s mouse model

BackgroundAlzheimer’s disease (AD) is characterized by a progressive loss of memory that cannot be efficiently managed by currently available AD therapeutics. So far, most treatments for AD that have the potential to improve memory target neural circuits to protect their integrity. However, the vulnerable neural circuits and their dynamic remodeling during AD progression remain largely undefined.MethodsCircuit-based approaches, including anterograde and retrograde tracing, slice electrophysiology, and fiber photometry, were used to investigate the dynamic structural and functional remodeling of a GABAergic circuit projected from the medial septum (MS) to the dentate gyrus (DG) in 3xTg-AD mice during AD progression.ResultsWe identified a long-distance GABAergic circuit that couples highly connected MS and DG GABAergic neurons during spatial memory encoding. Furthermore, we found hyperactivity of DG interneurons during early AD, which persisted into late AD stages. Interestingly, MS GABAergic projections developed a series of adaptive strategies to combat DG interneuron hyperactivity. During early-stage AD, MS-DG GABAergic projections exhibit increased inhibitory synaptic strength onto DG interneurons to inhibit their activities. During late-stage AD, MS-DG GABAergic projections form higher anatomical connectivity with DG interneurons and exhibit aberrant outgrowth to increase the inhibition onto DG interneurons.ConclusionWe report the structural and functional remodeling of the MS-DG GABAergic circuit during disease progression in 3xTg-AD mice. Dynamic MS-DG GABAergic circuit remodeling represents a compensatory mechanism to combat DG interneuron hyperactivity induced by reduced GABA transmission.

Identification of a GABAergic neural circuit governing leptin signaling deficiency-induced obesity.

The hormone leptin is known to robustly suppress food intake by acting upon the leptin receptor (LepR) signaling system residing within the agouti-related protein (AgRP) neurons of the hypothalamus. However, clinical studies indicate that leptin is undesirable as a therapeutic regiment for obesity, which is at least partly attributed to the poorly understood complex secondary structure and key signaling mechanism of the leptin-responsive neural circuit. Here, we show that the LepR-expressing portal neurons send GABAergic projections to a cohort of α3-GABAA receptor expressing neurons within the dorsomedial hypothalamic nucleus (DMH) for the control of leptin-mediated obesity phenotype. We identified the DMH as a key brain region that contributes to the regulation of leptin-mediated feeding. Acute activation of the GABAergic AgRP-DMH circuit promoted food intake and glucose intolerance, while activation of post-synaptic MC4R neurons in the DMH elicited exactly opposite phenotypes. Rapid deletion of LepR from AgRP neurons caused an obesity phenotype which can be rescued by blockage of GABAA receptor in the DMH. Consistent with behavioral results, these DMH neurons displayed suppressed neural activities in response to hunger or hyperglycemia. Furthermore, we identified that α3-GABAA receptor signaling within the DMH exerts potent bi-directional regulation of the central effects of leptin on feeding and body weight. Together, our results demonstrate a novel GABAergic neural circuit governing leptin-mediated feeding and energy balance via a unique α3-GABAA signaling within the secondary leptin-responsive neural circuit, constituting a new avenue for therapeutic interventions in the treatment of obesity and associated comorbidities.

Microglial phagocytosis mediates long-term restructuring of spinal GABAergic circuits following early life injury

Peripheral injury during the early postnatal period alters the somatosensory system, leading to behavioural hyperalgesia upon re-injury in adulthood. Spinal microglia have been implicated as the cellular mediators of this phenomenon, but the mechanism is unclear. We hypothesised that neonatal injury (1) alters microglial phagocytosis of synapses in the dorsal horn leading to long-term structural changes in neurons, and/or (2) trains microglia, leading to a stronger microglial response after re-injury in adulthood. Using hindpaw surgical incision as a model we showed that microglial density and phagocytosis increased in the dorsal horn region innervated by the hindpaw. Dorsal horn microglia increased engulfment of synapses following injury, with a preference for those expressing the vesicular GABA transporter VGAT and primary afferent A-fibre terminals in neonates. This led to a long-term reduction of VGAT density in the dorsal horn and reduced microglial phagocytosis of VGLUT2 terminals. We also saw an increase in apoptosis following neonatal injury, which was not limited to the dorsal horn suggesting that larger circuit wide changes are happening.In adults, hindpaw incision increased microglial engulfment of predominantly VGAT synapses but did not alter the engulfment of A-fibres. This engulfment was not affected by prior neonatal injury, suggesting that microglial phagocytosis was not trained. These results highlight microglial phagocytosis in the dorsal horn as an important physiological response towards peripheral injury with potential long-term consequences and reveals differences in microglial responses between neonates and adults.

The hippocampus associated GABAergic neural network impairment in early-stage of Alzheimer's disease.

Alzheimer's disease (AD) is the commonest neurodegenerative disease with slow progression. Pieces of evidence suggest that the GABAergic system is impaired in the early stage of AD, leading to hippocampal neuron over-activity and further leading to memory and cognitive impairment in patients with AD. However, the precise impairment mechanism of the GABAergic system on the pathogenesis of AD is still unclear. The impairment of neural networks associated with the GABAergic system is tightly associated with AD. Therefore, we describe the roles played by hippocampus-related GABAergic circuits and their impairments in AD neuropathology. In addition, we give our understand on the process from GABAergic circuit impairment to cognitive and memory impairment, since recent studies on astrocyte in AD plays an important role behind cognition dysfunction caused by GABAergic circuit impairment, which helps better understand the GABAergic system and could open up innovative AD therapy.

The Boy in the Borstal: Gene Hunting, Dopaminergic Dogma, and the Science of Schizophrenia

The Boy in the Borstal: Gene Hunting, Dopaminergic Dogma, and the Science of Schizophrenia

Neurophysiological assessment of cortical activity in DEPDC5- and NPRL3-related epileptic mTORopathies

BackgroundMutations in the GATOR1 complex genes, DEPDC5 and NPRL3, play a major role in the development of lesional and non-lesional focal epilepsy through increased mTORC1 signalling. We aimed to assess the effects of mTORC1 hyperactivation on GABAergic inhibitory circuits, in 3 and 5 individuals carrying DEPDC5 and NPRL3 mutations respectively using a multimodal approach including transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy (MRS), and electroencephalography (EEG).ResultsInhibitory functions probed by TMS and MRS showed no effect of mutations on cortical GABAergic receptor-mediated inhibition and GABA concentration, in both cortical and subcortical regions. However, stronger EEG theta oscillations and stronger and more synchronous gamma oscillations were observed in DEPDC5 and NPRL3 mutations carriers.ConclusionsThese results suggest that DEPDC5 and NPRL3-related epileptic mTORopathies may not directly modulate GABAergic functions but are nonetheless characterized by a stronger neural entrainment that may be reflective of a cortical hyperexcitability mediated by increased mTORC1 signaling.

Cortical inhibitory but not excitatory synaptic transmission and circuit refinement are altered after the deletion of NMDA receptors during early development

Neurons in the cerebral cortex form excitatory and inhibitory circuits with specific laminar locations. The mechanisms underlying the development of these spatially specific circuits is not fully understood. To test if postsynaptic N-methyl-D-aspartate (NMDA) receptors on excitatory neurons are required for the development of specific circuits to these neurons, we genetically ablated NMDA receptors from a subset of excitatory neurons in the temporal association cortex (TeA) through in utero electroporation and assessed the intracortical circuits connecting to L5 neurons through in vitro whole-cell patch clamp recordings coupled with laser-scanning photostimulation (LSPS). In NMDAR knockout neurons, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated connections were largely intact. In contrast both LSPS and mini-IPSC recordings revealed that γ-aminobutyric acid type A (GABAA) receptor-mediated connections were impaired in NMDAR knockout neurons. These results suggest that postsynaptic NMDA receptors are important for the development of GABAergic circuits.

Mechanisms of Hebbian-like plasticity in the ventral premotor - primary motor network.

The functional connection between ventral premotor cortex (PMv) and primary motor cortex (M1) is critical for the organization of goal-directed actions. Repeated activation of this connection by means of cortico-cortical paired associative stimulation (cc-PAS), a transcranial magnetic stimulation (TMS) protocol, may induce Hebbian-like plasticity. However, the physiological modifications produced by Hebbian-like plasticity in the PMv-M1 network are poorly understood. To fill this gap, we investigated the effects of cc-PAS on PMv-M1 circuits. We hypothesized that specific interactions would occur with I2 -wave interneurons as measured by the short intracortical facilitation protocol (SICF). We used different paired-pulse TMS protocols to examine the effects of PMv-M1 cc-PAS on SICF, on GABAergic circuits as measured by short (SICI) and long (LICI) intracortical inhibition protocols, and varied the current direction in M1 to target different M1 neuronal populations. Finally, we examined the effects of cc-PAS on PMv-M1 connectivity using a dual coil approach. We found that PMv-M1 cc-PAS induces both a long-term potentiation (LTP)- or long-term depression (LTD)-like after-effect in M1 neuronal activity that is strongly associated with a bidirectional-specific change in I2 -wave activity (SICF=2.5ms ISI). Moreover, cc-PAS induces a specific modulation of the LICI circuit and separately modulates PMv-M1 connectivity. We suggest that plasticity within the PMv-M1 circuit is mediated by a selective mechanism exerted by PMv on M1 by targeting I2 -wave interneurons. These results provide new mechanistic insights into how PMv modulates M1 activity that are relevant for the design of brain stimulation protocols in health and disease. KEY POINTS: The I2 -wave is specifically modulated by the induction of ventral premotor cortex - primary motor cortex (PMv-M1) plasticity. After PMv-M1 cortico-cortical paired associative stimulation (cc-PAS), corticospinal excitability correlates negatively with I2 -wave amplitude. Different cc-PAS coil orientations can lead to a long-term potentiation- or long-term depression-like after-effect in M1.

A cluster of mesopontine GABAergic neurons suppresses REM sleep and curbs cataplexy

Physiological rapid eye movement (REM) sleep termination is vital for initiating non-REM (NREM) sleep or arousal, whereas the suppression of excessive REM sleep is promising in treating narcolepsy. However, the neuronal mechanisms controlling REM sleep termination and keeping sleep continuation remain largely unknown. Here, we reveal a key brainstem region of GABAergic neurons in the control of both physiological REM sleep and cataplexy. Using fiber photometry and optic tetrode recording, we characterized the dorsal part of the deep mesencephalic nucleus (dDpMe) GABAergic neurons as REM relatively inactive and two different firing patterns under spontaneous sleep–wake cycles. Next, we investigated the roles of dDpMe GABAergic neuronal circuits in brain state regulation using optogenetics, RNA interference technology, and celltype-specific lesion. Physiologically, dDpMe GABAergic neurons causally suppressed REM sleep and promoted NREM sleep through the sublaterodorsal nucleus and lateral hypothalamus. In-depth studies of neural circuits revealed that sublaterodorsal nucleus glutamatergic neurons were essential for REM sleep termination by dDpMe GABAergic neurons. In addition, dDpMe GABAergic neurons efficiently suppressed cataplexy in a rodent model. Our results demonstrated that dDpMe GABAergic neurons controlled REM sleep termination along with REM/NREM transitions and represented a novel potential target to treat narcolepsy.

Assessing HD-EEG functional connectivity states using a human brain computational model

Objective. Electro/Magnetoencephalography (EEG/MEG) source-space network analysis is increasingly recognized as a powerful tool for tracking fast electrophysiological brain dynamics. However, an objective and quantitative evaluation of pipeline steps is challenging due to the lack of realistic ‘controlled’ data. Here, our aim is two-folded: (a) provide a quantitative assessment of the advantages and limitations of the analyzed techniques and (b) introduce (and share) a complete framework that can be used to optimize the entire pipeline of EEG/MEG source connectivity. Approach. We used a human brain computational model containing both physiologically based cellular GABAergic and Glutamatergic circuits coupled through Diffusion Tensor Imaging, to generate high-density EEG recordings. We designed a scenario of successive gamma-band oscillations in distinct cortical areas to emulate a virtual picture-naming task. We identified fast time-varying network states and quantified the performance of the key steps involved in the pipeline: (a) inverse models to reconstruct cortical-level sources, (b) functional connectivity measures to compute statistical interdependency between regional signals, and (c) dimensionality reduction methods to derive dominant brain network states (BNS). Main results. Using a systematic evaluation of the different decomposition techniques, results show significant variability among tested algorithms in terms of spatial and temporal accuracy. We outlined the spatial precision, the temporal sensitivity, and the global accuracy of the extracted BNS relative to each method. Our findings suggest a good performance of weighted minimum norm estimate/ Phase Locking Value combination to elucidate the appropriate functional networks and ICA techniques to derive relevant dynamic BNS. Significance. We suggest using such brain models to go further in the evaluation of the different steps and parameters involved in the EEG/MEG source-space network analysis. This can reduce the empirical selection of inverse model, connectivity measure, and dimensionality reduction method as some of the methods can have a considerable impact on the results and interpretation.

Visual-area-specific tonic modulation of GABA release by endocannabinoids sets the activity and coordination of neocortical principal neurons.

SummaryPerisomatic inhibition of pyramidal neurons (PNs) coordinates cortical network activity during sensory processing, and this role is mainly attributed to parvalbumin-expressing basket cells (BCs). However, cannabinoid receptor type 1 (CB1)-expressing interneurons are also BCs, but the connectivity and function of these elusive but prominent neocortical inhibitory neurons are unclear. We find that their connectivity pattern is visual area specific. Persistently active CB1 signaling suppresses GABA release from CB1 BCs in the medial secondary visual cortex (V2M), but not in the primary visual cortex (V1). Accordingly, in vivo, tonic CB1 signaling is responsible for higher but less coordinated PN activity in the V2M than in the V1. These differential firing dynamics in the V1 and V2M can be captured by a computational network model that incorporates visual-area-specific properties. Our results indicate a differential CB1-mediated mechanism controlling PN activity, suggesting an alternative connectivity scheme of a specific GABAergic circuit in different cortical areas.

GABAergic circuits of the basolateral amygdala and generation of anxiety after traumatic brain injury.

Traumatic brain injury (TBI) has reached epidemic proportions around the world and is a major public health concern in the United States. Approximately 2.8 million individuals sustain a traumatic brain injury and are treated in an Emergency Department yearly in the U.S., and about 50,000 of them die. Persistent symptoms develop in 10-15% of the cases including neuropsychiatric disorders. Anxiety is the second most common neuropsychiatric disorder that develops in those with persistent neuropsychiatric symptoms after TBI. Abnormalities or atrophy in the temporal lobe has been shown in the overwhelming number of TBI cases. The basolateral amygdala (BLA), a temporal lobe structure that consolidates, stores and generates fear and anxiety-based behavioral outputs, is a critical brain region in the anxiety circuitry. In this review, we sought to capture studies that characterized the relationship between human post-traumatic anxiety and structural/functional alterations in the amygdala. We compared the human findings with results obtained with a reproducible mild TBI animal model that demonstrated a direct relationship between the alterations in the BLA and an anxiety-like phenotype. From this analysis, both preliminary insights, and gaps in knowledge, have emerged which may open new directions for the development of rational and more efficacious treatments.

The role of inhibitory circuits in hippocampal memory processing.

GABAergic inhibitory circuits play an essential role in coordinating various hippocampal functions. Several decades of work dedicated to a thorough characterization of hippocampal inhibitory populations have highlighted how specific types of interneuron can contribute to network activity. Recent studies have used genetically targeted recordings and peturbations of activity during memory-related behaviours to determine how interneurons that inhibit distinct subcellular domains of principal cells or specialize in principal cell disinhibition may sculpt hippocampal memory. These studies highlight unique contributions of distinct interneuron types to the temporal binding of hippocampal ensembles, synaptic plasticity and the acquisition of spatial and contextual information. Here, we review the current state of knowledge around hippocampal inhibition and memory by discussing the multifaceted roles of populations of inhibitory cells at different stages of hippocampal mnemonic processing.

Glutamate released by Cajal-Retzius cells impacts specific hippocampal circuits and behaviors.

SUMMARYThe impact of Cajal-Retzius cells on the regulation of hippocampal circuits and related behaviors is unresolved. Here, we directly address this issue by impairing the glutamatergic output of Cajal-Retzius cells with the conditional ablation of vGluT2, which is their main vesicular glutamate transporter. Although two distinct conditional knockout lines do not reveal major alterations in hippocampal-layer organization and dendritic length of principal neurons or GABAergic cells, we find parallel deficits in specific hippocampal-dependent behaviors and in their putative underlying microcircuits. First, conditional knockout animals show increased innate anxiety and decreased feedforward GABAergic inhibition on dentate gyrus granule cells. Second, we observe impaired spatial memory processing, which is associated with decreased spine density and reduced AMPA/NMDA ratio of postsynaptic responses at the perforant- and entorhino-hippocampal pathways. We conclude that glutamate synaptically released by Cajal-Retzius cells is critical for the regulation of hippocampal microcircuits and specific types of behaviors.

Ripple-selective GABAergic projection cells in the hippocampus

Ripples are brief high-frequency electrographic events with important roles in episodic memory. However, the invivo circuit mechanisms coordinating ripple-related activity among local and distant neuronal ensembles are not well understood. Here, we define key characteristics of a long-distance projecting GABAergic cell group in the mouse hippocampus that selectively exhibits high-frequency firing during ripples while staying largely silent during theta-associated states when most other GABAergic cells are active. The high ripple-associated firing commenced before ripple onset and reached its maximum before ripple peak, with the signature theta-OFF, ripple-ON firing pattern being preserved across awake and sleep states. Controlled by septal GABAergic, cholinergic, and CA3 glutamatergic inputs, these ripple-selective cells innervate parvalbumin and cholecystokinin-expressing local interneurons while also targeting a variety of extra-hippocampal regions. These results demonstrate the existence of a hippocampal GABAergic circuit element that is uniquely positioned to coordinate ripple-related neuronal dynamics across neuronal assemblies.