Network Excitability Research Articles

Effects of nicotinic antagonists on working memory performance in young rhesus monkeys

Acetylcholine plays a pivotal neuromodulatory role in the brain, influencing neuronal activity and cognitive function. Nicotinic receptors, particularly α7 and α4β2 receptors, modulate firing of dorsolateral prefrontal (dlPFC) excitatory networks that underlie successful working memory function. Minimal work however has been done examining working memory following systemic blockade of nicotinic receptor systems in nonhuman primates, limiting the ability to explore interactions of other neuromodulatory influences with working memory impairment caused by nicotinic antagonism. In this study, we investigated working memory performance after administering three nicotinic antagonists, mecamylamine, methyllycaconitine, and dihydro-β-erythroidine, in rhesus macaques tested in a spatial delayed response task. Surprisingly, we found that no nicotinic antagonist significantly impaired delayed response performance compared to vehicle. In contrast, the muscarinic antagonist scopolamine reliably impaired delayed response performance in all monkeys tested. These findings suggest there are some limitations on using systemic nicotinic antagonists to probe the involvement of nicotinic receptors in aspects of dlPFC-dependent working memory function, necessitating alternative strategies to understand the role of this system in cognitive deficits seen in aging and neurodegenerative disease.

Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers.

Intracellular amyloid beta oligomer (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking iAβo with an increase in neuronal excitability has been reported. Here, the effects of human AD brain‐derived (h‐iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential firing were investigated in hippocampal neurons. Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor‐mediated current. Both effects were PKC‐dependent. Parallel recordings of synaptic currents and nitric oxide (NO)‐associated fluorescence showed that the increased frequency, related to pre‐synaptic release, was dependent on a NO‐mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current‐clamp recordings suggested that iAβo increased neuronal excitability via AMPA‐driven synaptic activity without altering membrane intrinsic properties. These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic‐driven mechanism and offers an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

Effects of hyperventilation with face mask on brain network in patients with epilepsy

ObjectivesDuring the ongoing pandemic of COVID-19, wearing face masks was recommended, including patients with epilepsy doing the hyperventilation (HV) test during electroencephalogram (EEG) examination somewhere. However, evidence was still limited about the effect of HV with face mask on cortical excitability of patients with epilepsy. The motivation of this work is to make use of the graph theory of EEG to characterize the cortical excitability of patients with epilepsy when they did HV under the condition wearing a surgical face mask. MethodsWe recruited 19 patients with epilepsy and 17 normal controls. All of participants completed two HV experiments, including HV with face mask (HV+) and HV without a mask (HV). The interval was 30 min and the sequence was random. Each experiment consisted of three segments: resting EEG, EEG of HV, and EEG of post-HV. EEG were recorded successively during each experiment. Participants were asked to evaluate the discomfort degree using a questionnaire when every HV is completed. ResultsAll of the participants felt more uncomfortable after HV + . Moreover, not only HV decreased small-worldness index in patients with epilepsy, but also HV + significantly increased the clustering coefficient in patients with epilepsy. Importantly, the three-way of Mask*HV*Epilepsy showed interaction in the clustering coefficient in the delta band, as well as in the path length and the small-worldness index in the theta band. ConclusionsThe results of this study indicated that patients with epilepsy showed the increased excitability of brain network during HV + . We should pay more attention to the adverse effect on brain network excitability caused by HV + in patients with epilepsy. In the clinical practice under the COVID-19 pandemic, it is important that the wearing face mask remain cautious for the individuals with epilepsy when they carried out HV behavior such as exercise (e.g., running, etc.).

Regulation of the voltage-dependent sodium channel NaV1.1 by AKT1

The voltage-sensitive sodium channel NaV1.1 plays a critical role in regulating excitability of GABAergic neurons and mutations in the corresponding gene are associated to Dravet syndrome and other forms of epilepsy. The activity of this channel is regulated by several protein kinases. To identify novel regulatory kinases we screened a library of activated kinases and we found that AKT1 was able to directly phosphorylate NaV1.1. In vitro kinase assays revealed that the phosphorylation site was located in the C-terminal part of the large intracellular loop connecting domains I and II of NaV1.1, a region that is known to be targeted by other kinases like PKA and PKC. Electrophysiological recordings revealed that activated AKT1 strongly reduced peak Na+ currents and displaced the inactivation curve to more negative potentials in HEK-293 cell stably expressing NaV1.1. These alterations in current amplitude and steady-state inactivation were mimicked by SC79, a specific activator of AKT1, and largely reverted by triciribine, a selective inhibitor. Neurons expressing endogenous NaV1.1 in primary cultures were identified by expressing a fluorescent protein under the NaV1.1 promoter. There, we also observed a strong decrease in the current amplitude after addition of SC79, but small effects on the inactivation parameters. Altogether, we propose a novel mechanism that might regulate the excitability of neural networks in response to AKT1, a kinase that plays a pivotal role under physiological and pathological conditions, including epileptogenesis.

Zearalenone alters the excitability of rat neuronal networks after acute in vitro exposure

Zearalenone (ZEA) is a mycotoxin produced by Fusarium species, detectable in various cereals and processed food products worldwide. ZEA displays a significant estrogenic activity, thus its main health risk is the interference with sexual maturation and reproduction processes. However, in addition to being key hormonal regulators of reproductive function, estrogenic compounds have a widespread role in brain, as neurotrophic and neuroprotective factors, and they may influence the activity of several brain areas not directly linked to reproduction, as well. Therefore, in the present study, acute effects of ZEA were studied on certain neuronal functions in rats.Experiments were performed on rat brain slices or live rats. Slices were incubated in ZEA-containing (10–100 μM) solution for 30 min. Electrically evoked and spontaneous field potentials were studied in the neocortex and in the hippocampus. At higher concentrations, ZEA incubation of the slices altered excitability and the pattern of epileptiform activity in neocortex and inhibited the development of LTP in hippocampus.For the verification of these in vitro results, in vivo electrophysiological and immunohistochemical investigations were also performed. ZEA was administered systemically (5 mg/kg, i.p.) to male rats and somatosensory evoked potentials and neuronal activation studied by c-fos expression were analyzed. No neuronal activation could be demonstrated in the hippocampus within 2 h of the injection. In the somatosensory cortex, ZEA did not change in vivo evoked potential parameters, but the activation of a small neuronal population could be demonstrated with the c-fos technique in this brain area. This result could be associated with the ZEA-induced alteration of epileptiform activity observed in vitro.Altogether, the toxin altered the excitability and plasticity of neuronal networks after direct treatment in slices, but the effects were less prominent on the given brain areas after systemic treatment in vivo. A probable explanation for the partial lack of in vivo effects may be that after a single injection, ZEA did not cross the blood-brain barrier at sufficient rate to allow the build-up of comparable concentrations in the investigated brain areas. However, in case of compromised blood-brain barrier functions or long-term repeated exposure, alterations in cortical and hippocampal functions cannot be ruled out.

Lateralized Decrease of Parvalbumin+ Cells in the Somatosensory Cortex of ASD Models Is Correlated with Unilateral Tactile Hypersensitivity.

Inhibitory control of excitatory networks contributes to cortical functions. Increasing evidence indicates that parvalbumin (PV+)-expressing basket cells (BCs) are a major player in maintaining the balance between excitation (E) and inhibition (I). Disruption of E/I balance in cortical networks is believed to be a hallmark of autism spectrum disorder (ASD). Here, we report a lateralized decrease in the number of PV+ BCs in L2/3 of the somatosensory cortex in the dominant hemisphere of Shank3-/- and Cntnap2-/- mouse models of ASD. The dominant hemisphere was identified during a reaching task to establish each animal's dominant forepaw. Double labeling with anti-PV antibody and a biotinylated lectin (Vicia villosa lectin [VVA]) showed that the number of BCs was not different but rather, some BCs did not express PV (PV-), resulting in an elevated number of PV- VVA+ BCs. Finally, we showed that dominant hindpaws had higher mechanical sensitivity when compared with the other hindpaws. This mechanical hypersensitivity in the dominant paw strongly correlated with the decrease in the number of PV+ interneurons and reduced PV expression in the corresponding cortex. Together, these results suggest that the hypersensitivity in ASD patients could be due to decreased inhibitory inputs to the dominant somatosensory cortex.

Motor behavior: A feedforward circuit for zebrafish escape

A recent study of motor control in zebrafish demonstrates the critical role of an excitatory neural relay network in the transformation of a unilateral turn command into a subsequent bilateral swim signal. A rapid and smooth transition between these motor phases is critical for successfully escaping danger.

Kv1.1 channels mediate network excitability and feed-forward inhibition in local amygdala circuits

Kv1.1 containing potassium channels play crucial roles towards dampening neuronal excitability. Mice lacking Kv1.1 subunits (Kcna1−/−) display recurrent spontaneous seizures and often exhibit sudden unexpected death. Seizures in Kcna1−/− mice resemble those in well-characterized models of temporal lobe epilepsy known to involve limbic brain regions and spontaneous seizures result in enhanced cFos expression and neuronal death in the amygdala. Yet, the functional alterations leading to amygdala hyperexcitability have not been identified. In this study, we used Kcna1−/− mice to examine the contributions of Kv1.1 subunits to excitability in neuronal subtypes from basolateral (BLA) and central lateral (CeL) amygdala known to exhibit distinct firing patterns. We also analyzed synaptic transmission properties in an amygdala local circuit predicted to be involved in epilepsy-related comorbidities. Our data implicate Kv1.1 subunits in controlling spontaneous excitatory synaptic activity in BLA pyramidal neurons. In the CeL, Kv1.1 loss enhances intrinsic excitability and impairs inhibitory synaptic transmission, notably resulting in dysfunction of feed-forward inhibition, a critical mechanism for controlling spike timing. Overall, we find inhibitory control of CeL interneurons is reduced in Kcna1−/− mice suggesting that basal inhibitory network functioning is less able to prevent recurrent hyperexcitation related to seizures.

Adenosine A2A Receptors Contribute to the Radial Migration of Cortical Projection Neurons through the Regulation of Neuronal Polarization and Axon Formation.

Cortical interneurons born in the subpallium reach the cortex through tangential migration, whereas pyramidal cells reach their final position by radial migration. Purinergic signaling via P2Y1 receptors controls the migration of intermediate precursor cells from the ventricular zone to the subventricular zone. It was also reported that the blockade of A2A receptors (A2AR) controls the tangential migration of somatostatin+ interneurons. Here we found that A2AR control radial migration of cortical projection neurons. In A2AR-knockout (KO) mouse embryos or naïve mouse embryos exposed to an A2AR antagonist, we observed an accumulation of early-born migrating neurons in the lower intermediate zone at late embryogenesis. In utero knockdown of A2AR also caused an accumulation of neurons at the lower intermediate zone before birth. This entails the presently identified ability of A2AR to promote multipolar-bipolar transition and axon formation, critical for the transition of migrating neurons from the intermediate zone to the cortical plate. This effect seems to require extracellular ATP-derived adenosine since a similar accumulation of neurons at the lower intermediate zone was observed in mice lacking ecto-5'-nucleotidase (CD73-KO). These findings frame adenosine as a fine-tune regulator of the wiring of cortical inhibitory and excitatory networks.

Sex-dependent expression of N-cadherin-GluA1 pathway-related molecules in the prefrontal cortex mediates anxiety-like behavior in male offspring following prenatal stress

Prenatal stress (PS) affects neurodevelopment and increases the risk for anxiety in adolescence in male offspring, but the mechanism is still unclear. N-Cadherin regulates the expression of AMPA receptors (AMPARs), which mediate anxiety by modulating network excitability in the prefrontal cortex (PFC). Our results revealed that in adolescent male, but not female, offspring rats, PS induced anxiety-like behavior, as assessed by the open field test (OFT). Furthermore, N-cadherin and AMPAR subunit GluA1 were colocalized in the PFC, and the expression of the N-cadherin and the GluA1 decreased following PS exposure in male offspring rats. We also found that the AMPAR agonist CX546 did not alleviate anxiety-like behavior in adolescent male offspring rats; however, it increased the expression of GluA1 in the PFC but did not alter the expression of N-cadherin. In conclusion, our study suggested that the N-cadherin-GluA1 pathway in the PFC mediates anxiety-like behavior in adolescent male offspring rats and that N-cadherin might be required for sex differences in the effect of PS on adolescent offspring.

Maternal caffeine consumption and childhood behavioural and neurocognitive development: A focused narrative review

Rationale: The majority of pregnant women regularly consume caffeine, a habit-forming substance of no nutritional value for mother or baby. Objectives: To examine evidence of association between maternal caffeine consumption and childhood behavioural and neurocognitive development, and to consider the soundness of current health guidance concerning the consumption of caffeine during pregnancy. Methods: Database searches identified a large pool of peer-reviewed articles, which when culled for relevance yielded a modest corpus of animal and human research for inclusion in this focussed narrative review of potential caffeine-related threats to childhood behavioural and neurocognitive development. Results: High biological plausibility of potential harm from maternal caffeine exposure indicated by early animal research is confirmed by more recent animal studies that sought to mimic human consumption patterns. Reported negative outcomes include increased neuronal network excitability and susceptibility to seizures in offspring, and disruptions to electrophysiological activity, learning, and memory. In contrast, human observational studies have yielded inconsistent findings. Some studies have reported evidence of negative behavioural and neurocognitive outcomes, including hyperkinetic disorder, attention deficit disorder, and intelligence level in preschool- and elementary-aged children. Other studies, however, reported no associations with maternal caffeine consumption for similar parameters. Conclusions: Current understanding of caffeine-related increased risk of harm for childhood development is limited due to inconsistent findings from human research. However, persistent reports of possible negative outcomes indicate high priority need for further research. In the meantime, the cumulative scientific evidence supports advice to pregnant women and women contemplating pregnancy to avoid caffeine.

From Physiology to Pathology of Cortico-Thalamo-Cortical Oscillations: Astroglia as a Target for Further Research.

The electrographic hallmark of childhood absence epilepsy (CAE) and other idiopathic forms of epilepsy are 2.5–4 Hz spike and wave discharges (SWDs) originating from abnormal electrical oscillations of the cortico-thalamo-cortical network. SWDs are generally associated with sudden and brief non-convulsive epileptic events mostly generating impairment of consciousness and correlating with attention and learning as well as cognitive deficits. To date, SWDs are known to arise from locally restricted imbalances of excitation and inhibition in the deep layers of the primary somatosensory cortex. SWDs propagate to the mostly GABAergic nucleus reticularis thalami (NRT) and the somatosensory thalamic nuclei that project back to the cortex, leading to the typical generalized spike and wave oscillations. Given their shared anatomical basis, SWDs have been originally considered the pathological transition of 11–16 Hz bursts of neural oscillatory activity (the so-called sleep spindles) occurring during Non-Rapid Eye Movement (NREM) sleep, but more recent research revealed fundamental functional differences between sleep spindles and SWDs, suggesting the latter could be more closely related to the slow (<1 Hz) oscillations alternating active (Up) and silent (Down) cortical activity and concomitantly occurring during NREM. Indeed, several lines of evidence support the fact that SWDs impair sleep architecture as well as sleep/wake cycles and sleep pressure, which, in turn, affect seizure circadian frequency and distribution. Given the accumulating evidence on the role of astroglia in the field of epilepsy in the modulation of excitation and inhibition in the brain as well as on the development of aberrant synchronous network activity, we aim at pointing at putative contributions of astrocytes to the physiology of slow-wave sleep and to the pathology of SWDs. Particularly, we will address the astroglial functions known to be involved in the control of network excitability and synchronicity and so far mainly addressed in the context of convulsive seizures, namely (i) interstitial fluid homeostasis, (ii) K+ clearance and neurotransmitter uptake from the extracellular space and the synaptic cleft, (iii) gap junction mechanical and functional coupling as well as hemichannel function, (iv) gliotransmission, (v) astroglial Ca2+ signaling and downstream effectors, (vi) reactive astrogliosis and cytokine release.

Dendritic spine density changes and homeostatic synaptic scaling: a meta-analysis of animal studies.

Mechanisms of homeostatic plasticity promote compensatory changes of cellular excitability in response to chronic changes in the network activity. This type of plasticity is essential for the maintenance of brain circuits and is involved in the regulation of neural regeneration and the progress of neurodegenerative disorders. One of the most studied homeostatic processes is synaptic scaling, where global synaptic adjustments take place to restore the neuronal firing rate to a physiological range by the modulation of synaptic receptors, neurotransmitters, and morphology. However, despite the comprehensive literature on the electrophysiological properties of homeostatic scaling, less is known about the structural adjustments that occur in the synapses and dendritic tree. In this study, we performed a meta-analysis of articles investigating the effects of chronic network excitation (synaptic downscaling) or inhibition (synaptic upscaling) on the dendritic spine density of neurons. Our results indicate that spine density is consistently reduced after protocols that induce synaptic scaling, independent of the intervention type. Then, we discuss the implication of our findings to the current knowledge on the morphological changes induced by homeostatic plasticity.

Regulation of perineuronal nets in the adult cortex by the activity of the cortical network.

Perineuronal net (PNN) accumulation around parvalbumin-expressing (PV) inhibitory interneurons marks the closure of critical periods of high plasticity, whereas PNN removal reinstates juvenile plasticity in the adult cortex. Using targeted chemogenetic in vivo approaches in the adult mouse visual cortex, we found that transient inhibition of PV interneurons, through metabotropic or ionotropic chemogenetic tools, induced PNN regression. Electroencephalographic recordings indicated that inhibition of PV interneurons did not elicit unbalanced network excitation. Likewise, inhibition of local excitatory neurons also induced PNN regression, whereas chemogenetic excitation of either PV or excitatory neurons did not reduce the PNN. We also observed that chemogenetically inhibited PV interneurons exhibited reduced PNN compared to their untransduced neighbors, and confirmed that single PV interneurons express multiple genes enabling individual regulation of their own PNN density. Our results indicate that PNN density is regulated in the adult cortex by local changes of network activity that can be triggered by modulation of PV interneurons. PNN regulation may provide adult cortical circuits with an activity-dependent mechanism to control their local remodeling.SIGNIFICANCE STATEMENTThe perineuronal net is an extracellular matrix, which accumulates around individual parvalbumin-expressing inhibitory neurons during postnatal development, and is seen as a barrier that prevents plasticity of neuronal circuits in the adult cerebral cortex. We found that transiently inhibiting parvalbumin-expressing or excitatory cortical neurons triggers a local decrease of perineuronal net density. Our results indicate that perineuronal nets are regulated in the adult cortex depending on the activity of local microcircuits. These findings uncover an activity-dependent mechanism by which adult cortical circuits may locally control their plasticity.

Consolidation of memory traces in cultured cortical networks requires low cholinergic tone, synchronized activity and high network excitability

In systems consolidation, encoded memories are replayed by the hippocampus during slow-wave sleep (SWS), and permanently stored in the neocortex. Declarative memory consolidation is believed to benefit from the oscillatory rhythms and low cholinergic tone observed in this sleep stage, but underlying mechanisms remain unclear. To clarify the role of cholinergic modulation and synchronized activity in memory consolidation, we applied repeated electrical stimulation in mature cultures of dissociated rat cortical neurons with high or low cholinergic tone, mimicking the cue replay observed during systems consolidation under distinct cholinergic concentrations. In the absence of cholinergic input, these cultures display activity patterns hallmarked by network bursts, synchronized events reminiscent of the low frequency oscillations observed during SWS. They display stable activity and connectivity, which mutually interact and achieve an equilibrium. Electrical stimulation reforms the equilibrium to include the stimulus response, a phenomenon interpreted as memory trace formation. Without cholinergic input, activity was burst-dominated. First application of a stimulus induced significant connectivity changes, while subsequent repetition no longer affected connectivity. Presenting a second stimulus at a different electrode had the same effect, whereas returning to the initial stimuli did not induce further connectivity alterations, indicating that the second stimulus did not erase the ‘memory trace’ of the first. Distinctively, cultures with high cholinergic tone displayed reduced network excitability and dispersed firing, and electrical stimulation did not induce significant connectivity changes. We conclude that low cholinergic tone facilitates memory formation and consolidation, possibly through enhanced network excitability. Network bursts or SWS oscillations may merely reflect high network excitability.

Regulation of stress-provoked aggressive behavior using endocannabinoids

Reactive impulsive aggression is characterized by outbursts of rage and violence when subjects encounter threatening stressful events. Although impulsive aggression and violence create a high-cost burden on health and society, relatively little is known about treatment. Early adolescent social isolation (SI) alters brain development and functions. It induces hyper-excitatory in the ventral hippocampus (vHip) to promote acute stress-provoked outbursts of aggression, referred to as impulsive aggression, in mouse models. Cannabinoid type 1 receptors (CB1Rs) act on presynaptic sites and suppress neurotransmitter release into synapses. Given that CB1R activation inhibits neurotransmitter releases and modulates excitatory network activity, we tested the hypothesis that CB1R activation reduces impulsive aggression in SI mice through decreasing excitatory activity in the vHip. Here, we report that CB1R agonists, WIN-552122 (WIN) or arachidonylcyclopropylamide (ACPA), ameliorated acute stress-provoked attack behavior in the resident-intruder test without affecting general locomotion activity. Increasing endocannabinoids (eCBs) by inhibiting degradation enzymes in the vHip reduced impulsive aggression, and the effect was blunted by administration of AM251, a CB1R antagonist. Acute stress in SI mice induced c-Fos expression, a marker of neuronal activation, on vHip neurons projecting to the ventromedial hypothalamus (VMH), a well-known brain area that controls attack behavior. eCB augmentation inhibited c-Fos expression in VMH-projecting vHip neurons surrounded by CB1Rs. These results suggest that enhancing eCB signaling in order to activate CB1Rs suppresses impulsive aggression via suppressing vHip→VMH neural activity and point to a role of CB1R activation in ameliorating impulsive aggression in adults who have had adverse experiences during early adolescence.

Effects of degree distributions in random networks of type-I neurons.

We consider large networks of theta neurons and use the Ott-Antonsen ansatz to derive degree-based mean-field equations governing the expected dynamics of the networks. Assuming random connectivity, we investigate the effects of varying the widths of the in- and out-degree distributions on the dynamics of excitatory or inhibitory synaptically coupled networks and gap junction coupled networks. For synaptically coupled networks, the dynamics are independent of the out-degree distribution. Broadening the in-degree distribution destroys oscillations in inhibitory networks and decreases the range of bistability in excitatory networks. For gap junction coupled neurons, broadening the degree distribution varies the values of parameters at which there is an onset of collective oscillations. Many of the results are shown to also occur in networks of more realistic neurons.

Rhythmogenic states of the respiratory network reveal differential opioid sensitivity

Opioid induced respiratory depression (OIRD) is the major cause of death associated with opioid use. Although mortality increases dose-dependently, variability in the opioid response makes opioids particularly dangerous. The variability may be partly explained by rhythmogenic properties of the preBötzinger Complex (preBötC), a region that constitutes the minimal circuitry necessary for breathing. At the core of rhythmogenesis are periodic inspiratory bursts that emerge from synchronized activity within the preBötC. Between each burst, excitation builds among a growing number of neurons that synchronize to form a burst. Implicated in this are network-based mechanisms between recurrently connected excitatory and inhibitory neurons, as well as intrinsic-based mechanisms involving intrinsically bursting neurons that express persistently active inward cation currents, such as the persistent sodium current (INaP). Importantly, these mechanisms are sensitive to neuromodulation and depend on network excitability. Here, we test the hypothesis that shifts in the relative rhythmogenic role of network- and intrinsic- based mechanisms allow the preBötC to operate along a continuum of states, and consequently modulates sensitivity to OIRD. Horizontal brainstem slices were exposed to varying concentrations of aCSF [K+] or pharmacological manipulation of INaP prior to bath-application of the µ-opioid receptor agonist DAMGO. The aCSF [K+] required to induce bursting varied amongst slices. 48% required 8mM [K+], 17% required 6.5mM [K+], 10% required 5mM [K+], and 24% were rhythmic at 3mM [K+]. Unexpectedly we found upon initiating bursting, further increases in aCSF [K+] either increased or decreased rhythm stability, following a bell curve. Along this curve, increasing [K+] initially increased rhythm stability from 5% to 30% stabilitymax. After stabilitymax was reached, further 2mM increases in [K+] decreased stability by -40%, -55%, -52%, and -71%. The trajectory of stability to increasing aCSF [K+] predicted OIRD sensitivity. Slices that did not reach stabilitymax by 8mM [K+] displayed high sensitivity to OIRD and were silenced prior to 200nM DAMGO. In contrast, slices that reached stabilitymax at aCSF [K+] lower than 8mM and destabilized in 8mM [K+], were only modestly suppressed (-32% change in burst frequency) by 200nM DAMGO. To test the role of INaP in OIRD sensitivity, INaP was suppressed with 400nM ATTX or 20µM Riluzole prior to DAMGO. Both treatments increased OIRD sensitivity and silenced all slices prior to 200nM DAMGO. Lastly, to test for a protective role of INaP against OIRD INaP was potentiated with 400nM veratridine before or after DAMGO. Veratridine prior to DAMGO prevented OIRD, whereas veratridine following OIRD rescued bursting. Our results suggest the primary mechanisms of rhythm generation are flexible, and shift based upon the amount of network excitability and intrinsic bursting. Further, changing these dynamic properties creates states of rhythmogenesis that become highly sensitive, or insensitive to OIRD.

Experience-Dependent Inhibitory Plasticity Is Mediated by CCK+ Basket Cells in the Developing Dentate Gyrus.

Early postnatal experience shapes both inhibitory and excitatory networks in the hippocampus. However, the underlying circuit plasticity is unclear. Using an enriched environment (EE) paradigm during the preweaning period in mice of either sex, we assessed the circuit plasticity of inhibitory cell types in the hippocampus. We found that cholecystokinin (CCK)-expressing basket cells strongly increased somatic inhibition on the excitatory granular cells (GCs) following EE, whereas another pivotal inhibitory cell type, parvalbumin (PV)-expressing cells, did not show changes. Using electrophysiological analysis and the use of cannabinoid receptor 1 (CB1R) agonist WIN 55 212-2, we demonstrate that the change in somatic inhibition from CCK+ neurons increases CB1R-mediated inhibition in the circuit. By inhibiting activity of the entorhinal cortex (EC) using a chemogenetic approach, we further demonstrate that the activity of the projections from the EC mediates the developmental assembly of CCK+ basket cell network. Altogether, our study places the experience-dependent remodeling of CCK+ basket cell innervation as a central process to adjust inhibition in the dentate gyrus and shows that cortical inputs to the hippocampus play an instructional role in controlling the refinement of the synaptic connections during the preweaning period.SIGNIFICANCE STATEMENT Brain plasticity is triggered by experience during postnatal brain development and shapes the maturing neural circuits. In humans, altered experience-dependent plasticity can have long-lasting detrimental effects on circuit function and lead to psychiatric disorders. Yet, the cellular mechanisms governing how early experience fine-tunes the maturing synaptic network is not fully understood. Here, taking advantage of an enrichment-housing paradigm, we unravel a new plasticity mechanism involved in the maintenance of the inhibitory to excitatory balance in the hippocampus. Our findings demonstrate that cortical activity instructs the assembly of the CCK+ basket cell network. Considering the importance of this specific cell type for learning and memory, experience-dependent remodeling of CCK+ cells may be a critical determinant for establishing appropriate neural networks.

Long-term effects of early postnatal nicotine exposure on cholinergic function in the mouse hippocampal CA1 region

In rodent models of smoking during pregnancy, early postnatal nicotine exposure results in impaired hippocampus-dependent memory, but the underlying mechanism remains elusive. Given that hippocampal cholinergic systems modulate memory and rapid development of hippocampal cholinergic systems occurs during nicotine exposure, here we investigated its impacts on cholinergic function. Both nicotinic and muscarinic activation produce transient or long-lasting depression of excitatory synaptic transmission in the hippocampal CA1 region. We found that postnatal nicotine exposure impairs both the induction and nicotinic modulation of NMDAR-dependent long-term depression (LTD). Activation of muscarinic receptors decreases excitatory synaptic transmission and CA1 network activity in both wild-type and α2 knockout mice. These muscarinic effects are still observed in nicotine-exposed mice. M1 muscarinic receptor activity is required for mGluR-dependent LTD. Early postnatal nicotine exposure has no effect on mGluR-dependent LTD induction, suggesting that it has no effect on the function of m1 muscarinic receptors involved in this form of LTD. Our results demonstrate that early postnatal nicotine exposure has more pronounced effects on nicotinic function than muscarinic function in the hippocampal CA1 region. Thus, impaired hippocampus-dependent memory may arise from the developmental disruption of nicotinic cholinergic systems in the hippocampal CA1 region.