Excitability Of Pyramidal Neurons Research Articles

Discrete subicular circuits control generalization of hippocampal seizures

Epilepsy is considered a circuit-level dysfunction associated with imbalanced excitation-inhibition, it is therapeutically necessary to identify key brain regions and related circuits in epilepsy. The subiculum is an essential participant in epileptic seizures, but the circuit mechanism underlying its role remains largely elusive. Here we deconstruct the diversity of subicular circuits in a mouse model of epilepsy. We find that excitatory subicular pyramidal neurons heterogeneously control the generalization of hippocampal seizures by projecting to different downstream regions. Notably, anterior thalamus-projecting subicular neurons bidirectionally mediate seizures, while entorhinal cortex-projecting subicular neurons act oppositely in seizure modulation. These two subpopulations are structurally and functionally dissociable. An intrinsically enhanced hyperpolarization-activated current and robust bursting intensity in anterior thalamus-projecting neurons facilitate synaptic transmission, thus contributing to the generalization of hippocampal seizures. These results demonstrate that subicular circuits have diverse roles in epilepsy, suggesting the necessity to precisely target specific subicular circuits for effective treatment of epilepsy.

EEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior.

Regulation of mRNA translation is essential for brain development and function. Translation elongation factor eEF2 acts as a molecular hub orchestrating various synaptic signals to protein synthesis control and participates in hippocampus-dependent cognitive functions. However, whether eEF2 regulates other behaviors in different brain regions has been unknown. Here, we construct a line of Eef2 heterozygous (HET) mice, which show a reduction in eEF2 and protein synthesis mainly in excitatory neurons of the prefrontal cortex. The mice also show lower spine density, reduced excitability, and AMPAR-mediated synaptic transmission in pyramidal neurons of the medial prefrontal cortex (mPFC). While HET mice exhibit normal learning and memory, they show defective social behavior and elevated anxiety. Knockdown of Eef2 in excitatory neurons of the mPFC specifically is sufficient to impair social novelty preference. Either chemogenetic activation of excitatory neurons in the mPFC or mPFC local infusion of the AMPAR potentiator PF-4778574 corrects the social novelty deficit of HET mice. Collectively, we identify a novel role for eEF2 in promoting prefrontal AMPAR-mediated synaptic transmission underlying social novelty behavior.

Evoked Cortical Depolarizations Before and After the Amyloid Plaque Accumulation: Voltage Imaging Study.

In Alzheimer's disease (AD), synaptic dysfunction is thought to occur many years before the onset of cognitive decline. Detecting synaptic dysfunctions at the earliest stage of AD would be desirable in both clinic and research settings. Population voltage imaging allows monitoring of synaptic depolarizations, to which calcium imaging is relatively blind. We developed an AD mouse model (APPswe/PS1dE9 background) expressing a genetically-encoded voltage indicator (GEVI) in the neocortex. GEVI was restricted to the excitatory pyramidal neurons (unlike the voltage-sensitive dyes). Expression of GEVI did not disrupt AD model formation of amyloid plaques. GEVI expression was stable in both AD model mice and Control (healthy) littermates (CTRL) over 247 days postnatal. Brain slices were stimulated in layer 2/3. From the evoked voltage waveforms, we extracted several parameters for comparison AD versus CTRL. Some parameters (e.g., temporal summation, refractoriness, and peak latency) were weak predictors, while other parameters (e.g., signal amplitude, attenuation with distance, and duration (half-width) of the evoked transients) were stronger predictors of the AD condition. Around postnatal age 150 days (P150) and especially at P200, synaptically-evoked voltage signals in brain slices were weaker in the AD groups versus the age- and sex-matched CTRL groups, suggesting an AD-mediated synaptic weakening that coincides with the accumulation of plaques. However, at the youngest ages examined, P40 and P80, the AD groups showed differentially stronger signals, suggesting "hyperexcitability" prior to the formation of plaques. Our results indicate bidirectional alterations in cortical physiology in AD model mice; occurring both prior (P40-80), and after (P150-200) the amyloid deposition.

Synchronization and oscillation behaviors of excitatory and inhibitory populations with spike-timing-dependent plasticity.

The effect of synaptic plasticity on the synchronization mechanism of the cerebral cortex has been a hot research topic over the past two decades. There are a great deal of literatures on excitatory pyramidal neurons, but the mechanism of interaction between the inhibitory interneurons is still under exploration. In this study, we consider a complex network consisting of excitatory (E) pyramidal neurons and inhibitory (I) interneurons interacting with chemical synapses through spike-timing-dependent plasticity(STDP). To study the effects of eSTDP and iSTDP on synchronization and oscillation behaviors emerged in an excitatory-inhibitory balanced network, we analyzed three different cases, a small-world network of purely excitatory neurons with eSTDP, a small-world network of purely inhibitory neurons with iSTDP and a small-world network with excitatory-inhibitory balanced neurons. By varying the number of inhibitory interneurons, and that of connected edges in a small-world network, and the coupling strength, these networks exhibit different synchronization and oscillation behaviors. We found that the eSTDP facilitates synchronization effectively, while iSTDP has no significant impact on it. In addition, eSTDP and iSTDP restrict the balance of the excitatory-inhibitory balanced neuronal network together and play a fundamental role in maintaining network stability and synchronization. They also can be used to guide the treatment and further research of neurodegenerative diseases.

Reduction of Excitatory Synaptic Transmission Efficacy in the Infralimbic Prefrontal Cortex Potentially Contributes to Impairment of Contextual Fear Memory Extinction in AgedMice.

Human beings are living longer than ever before and thecognitive decline experienced by aged adults, such as compromise in cognitive flexibility, has been attracting more and more attention. One such example is the aging-related impairment of memory extinction. However, its underlying neural basis, especially its functional basis at the synapse level, is largely unknown. This study verifies that Pavlovian contextual fear memory extinction is impaired in aged mice. Alarge body of previous studies has shown that the infralimbic prefrontal cortex (ilPFC) plays a pivotal role in memory extinction. Correspondingly, this study reveals an aging-related reduction in the efficacy of excitatory synaptic transmission onto the ilPFC pyramidal neurons via electrophysiology recordings. This study further suggests that this reduced excitation potentially contributes to the aging-related impairment of contextual fear memory extinction: chemogenetically suppressing the activity of the ilPFC pyramidal neurons in young mice impairs contextual fear memory extinction, whereas chemogenetically compensating forthe reduced excitation of the ilPFC pyramidal neurons in aged mice restores contextual fear memory extinction. This study identifies a functional synaptic plasticity in the ilPFC pyramidal neurons that potentially contributes to the aging-related impairment of contextual fear memory extinction, which would potentially help to develop a therapy to treat related cognitive decline in aged human adults.

Mechanism of carbachol-induced 40 Hz gamma oscillations and the effects of NMDA activation on oscillatory dynamics in a model of the CA3 subfield of the hippocampus

Gamma oscillations are a prominent feature of various neural systems, including the CA3 subfield of the hippocampus. In CA3, in vitro carbachol application induces ∼40 Hz gamma oscillations in the network of glutamatergic excitatory pyramidal neurons (PNs) and local GABAergic inhibitory neurons (INs). Activation of NMDA receptors within CA3 leads to an increase in the frequency of carbachol-induced oscillations to ∼60 Hz, a broadening of the distribution of individual oscillation cycle frequencies, and a decrease in the time lag between PN and IN spike bursts. In this work, we develop a biophysical integrate-and-fire model of the CA3 subfield, we show that the dynamics of our model are in concordance with physiological observations, and we provide computational support for the hypothesis that the ‘E-I’ mechanism is responsible for the emergence of ∼40 Hz gamma oscillations in the absence of NMDA activation. We then incorporate NMDA receptors into our CA3 model, and we show that our model exhibits the increase in gamma oscillation frequency, broadening of the cycle frequency distribution, and decrease in the time lag between PN and IN spike bursts observed experimentally. Remarkably, we find an inverse relationship in our model between the net NMDA current delivered to PNs and INs in an oscillation cycle and cycle frequency. Furthermore, we find a disparate effect of NMDA receptors on PNs versus INs – we show that NMDA receptors on INs tend to increase oscillation frequency, while NMDA receptors on PNs tend to slightly decrease or not affect oscillation frequency. We find that these observations can be explained if NMDA activity above a threshold level causes a shift in the mechanism underlying gamma oscillations; in the absence of NMDA receptors, the ‘E-I’ mechanism is primarily responsible for the generation of gamma oscillations (at 40 Hz), while when NMDA receptors are active, the mechanism of gamma oscillations shifts to the ‘I-I’ mechanism, and we argue that within the ‘I-I’ regime (which displays a higher baseline oscillation frequency of ∼60 Hz), slight changes in the level of NMDA activity are inversely related to cycle frequency.

Adaptation of prelimbic cortex mediated by IL-6/STAT3/Acp5 pathway contributes to the comorbidity of neuropathic pain and depression in rats

BackgroundThe adaption of brain region is fundamental to the development and maintenance of nervous system disorders. The prelimbic cortex (PrL) participates in the affective components of the pain sensation. However, whether and how the adaptation of PrL contributes to the comorbidity of neuropathic pain and depression are unknown.MethodsUsing resting-state functional magnetic resonance imaging (rs-fMRI), genetic knockdown or overexpression, we systematically investigated the activity of PrL region in the pathogenesis of neuropathic pain/depression comorbid using the combined approaches of immunohistochemistry, electrophysiology, and behavior.ResultsThe activity of PrL and the excitability of pyramidal neurons were decreased, and the osteoclastic tartrate-resistant acid phosphatase 5 (Acp5) expression in PrL neurons was upregulated following the acquisition of spared nerve injury (SNI)-induced comorbidity. Genetic knockdown of Acp5 in pyramidal neurons, but not parvalbumin (PV) neurons or somatostatin (SST) neurons, attenuated the decrease of spike number, depression-like behavior and mechanical allodynia in comorbidity rats. Overexpression of Acp5 in PrL pyramidal neurons decreased the spike number and induced the comorbid-like behavior in naïve rats. Moreover, the expression of interleukin-6 (IL-6), phosphorylated STAT3 (p-STAT3) and acetylated histone H3 (Ac-H3) were significantly increased following the acquisition of comorbidity in rats. Increased binding of STAT3 to the Acp5 gene promoter and the interaction between STAT3 and p300 enhanced acetylation of histone H3 and facilitated the transcription of Acp5 in PrL in the modeled rodents. Inhibition of IL-6/STAT3 pathway prevented the Acp5 upregulation and attenuated the comorbid-like behaviors in rats.ConclusionsThese data suggest that the adaptation of PrL mediated by IL-6/STAT3/Acp5 pathway contributed to the comorbidity of neuropathic pain/depression induced by SNI.

Vigilance and Behavioral State-Dependent Modulation of Cortical Neuronal Activity throughout the Sleep/Wake Cycle.

GABAergic inhibitory neurons, through their molecular, anatomic, and physiological diversity, provide a substrate for the modulation of ongoing cortical circuit activity throughout the sleep/wake cycle. Here, we investigated neuronal activity dynamics of parvalbumin (PV), vasoactive intestinal polypeptide (VIP), and somatostatin (SST) neurons in naturally sleeping head-restrained mice at the level of layer 2/3 of the primary somatosensory barrel cortex of mice. Through calcium imaging and targeted single-unit loose-patch or whole-cell recordings, we found that PV action potential firing activity was largest during both rapid eye movement (REM) and nonrapid eye movement (NREM) sleep stages, that VIP neurons were most active during REM sleep, and that the overall activity of SST neurons remained stable throughout the sleep/wake cycle. Analysis of neuronal activity dynamics uncovered rapid decreases in PV cell firing at wake onset followed by a progressive recovery during wake. Simultaneous local field potential (LFP) recordings further revealed that except for SST neurons, a large proportion of neurons were modulated by ongoing delta and theta oscillations. During NREM sleep spindles, PV and SST activity increased and decreased, respectively. Finally, we uncovered the presence of whisking behavior in mice during REM sleep and show that the activity of VIP and SST is differentially modulated during awake and sleeping whisking bouts, which may provide a neuronal substrate for internal brain representations occurring during sleep.SIGNIFICANCE STATEMENT In the sensory cortex, the balance between excitation and inhibition is believed to be highly dynamic throughout the sleep/wake cycle, shaping the response of cortical circuits to external stimuli while allowing the formation of newly encoded memory. Using in vivo two-photon calcium imaging or targeted single-unit recordings combined with LFP recordings, we describe the vigilance state and whisking-behavior-dependent activity of excitatory pyramidal and inhibitory GABAergic neurons in the supragranular layers of mouse somatosensory cortex. Interneuronal activity was found to be differentially modulated by ongoing delta and theta waves, sleep spindles, and a novel type of whisking observed during REM sleep, potentially providing a neuronal substrate for internal brain representations occurring during sleep.

Investigating the impact of 14‐3‐3 protein knockout on excitability of hippocampal CA1 pyramidal neurons

14‐3‐3 proteins are a family of regulatory proteins that are enriched at synaptic junctions. Many neurological and psychiatric disorders have also been linked to 14‐3‐3 protein dysfunctions. Our lab has previously shown that 14‐3‐3 protein functional knockout mice have reduced expression of synaptic proteins (including NMDA receptor subunits), deficits in hippocampal long‐term potentiation, and desynchronization in theta waves between hippocampus and prefrontal cortex. In addition, the 14‐3‐3 functional knockout mice exhibit behavior that correspond with the symptoms of psychiatric disorders such as schizophrenia. Recently, using cFos staining as an indicator, we identified an increase in activity in hippocampal CA1 and dentate gyrus neurons expressing the 14‐3‐3 inhibitor. However, it is not clear whether this increased neuronal activity is caused by altered synaptic activity, enhanced single cell excitability, or both. In this work, we are using slice electrophysiology and whole cell patch clamp to evaluate the impact of 14‐3‐3 inhibition on electrophysiological properties of hippocampal CA1 pyramidal neurons. To assess 14‐3‐3 knockout induced excitability changes, we measure differences in rheobase and firing rate between the 14‐3‐3 knockout mouse and their wild type control using current clamp. We are also using voltage clamp to identify changes in inward and/or outward current in these neurons. Additionally, we measure both miniature and spontaneous inhibitory and excitatory synaptic currents to assess potential alterations in synaptic input to the neurons in the 14‐3‐3 functional knockout mouse. We expect this study to provide critical insight that links the dysfunction of these regulatory proteins to the altered neuronal and/or synaptic activity, which may underline the neural circuitry and behavioral aberrations exhibited in these functional knockout mice.

Infralimbic cortex–medial striatum projections modulate the itch processing

Itch is an unpleasant sensation that induces the desire to scratch. Except for a sketchy map focusing on neural mechanisms underlying itch processing being drawn at the peripheral and spinal level over the past decades, the brain mechanisms remain poorly understood. Several previous studies indicated that anterior cingulate cortex (ACC) and prelimbic cortex (PrL), two subregions of the medial prefrontal cortex (mPFC) play an important role in regulating itch processing. However, the knowledge about whether infralimbic cortex (IL), another subregion of mPFC, is involved in modulating itch processing remains unclear. Here, we showed that the activity of IL excitatory pyramidal neurons was significantly elevated during itch-related scratching, and pharmacogenetic inhibition of IL pyramidal neurons significantly impaired itch-related scratching. Moreover, IL–medial striatum (MS) projections were verified as a critical neural pathway for modulating itch processing. Therefore, the present study firstly presents the regulatory function of IL pyramidal neurons during itch processing and also reveals that IL–MS projections are involved in modulating the itch processing.

5-HT2A receptor dysregulation in a schizophrenia relevant mouse model of NMDA receptor hypofunction

Blockade of N-methyl-D-aspartate receptors (NMDAR) is known to augment cortical serotonin 2A receptors (5-HT2ARs), which is implicated in psychosis. However, the pathways from NMDAR hypofunction to 5-HT2AR up-regulation are unclear. Here we addressed in mice whether genetic deletion of the indispensable NMDAR-subunit Grin1 principally in corticolimbic parvalbumin-positive fast-spiking interneurons, could up-regulate 5-HT2ARs leading to cortical hyper-excitability. First, in vivo local-field potential recording revealed that auditory cortex in Grin1 mutant mice became hyper-excitable upon exposure to acoustic click-train stimuli that release 5-HT in the cortex. This excitability increase was reproduced ex vivo where it consisted of an increased frequency of action potential (AP) firing in layer 2/3 pyramidal neurons of mutant auditory cortex. Application of the 5-HT2AR agonist TCB-2 produced similar results. The effect of click-trains was reversed by the 5-HT2AR antagonist M100907 both in vivo and ex vivo. Increase in AP frequency of pyramidal neurons was also reversed by application of Gαq protein inhibitor BIM-46187 and G protein-gated inwardly-rectifying K+ (GIRK) channel activator ML297. In fast-spiking interneurons, 5-HT2AR activation normally promotes GABA release, contributing to decreased excitability of postsynaptic pyramidal neurons, which was missing in the mutants. Moreover, unlike the controls, the GABAA receptor antagonist (+)-bicuculline had little effect on AP frequency of mutant pyramidal neurons, indicating a disinhibition state. These results suggest that the auditory-induced hyper-excitable state is conferred via GABA release deficits from Grin1-lacking interneurons leading to 5-HT2AR dysregulation and GIRK channel suppression in cortical pyramidal neurons, which could be involved in auditory psychosis.

Activation of TGR5 Ameliorates Streptozotocin-Induced Cognitive Impairment by Modulating Apoptosis, Neurogenesis, and Neuronal Firing.

Takeda G protein-coupled receptor 5 (TGR5) is the first known G protein-coupled receptor specific for bile acids and is recognized as a new and critical target for type 2 diabetes and metabolic syndrome. It is expressed in many brain regions associated with memory such as the hippocampus and frontal cortex. Here, we hypothesize that activation of TGR5 may ameliorate streptozotocin- (STZ-) induced cognitive impairment. The mouse model of cognitive impairment was established by a single intracerebroventricular (ICV) injection of STZ (3.0 mg/kg), and we found that TGR5 activation by its agonist INT-777 (1.5 or 3.0 μg/mouse, ICV injection) ameliorated spatial memory impairment in the Morris water maze and Y-maze tests. Importantly, INT-777 reversed STZ-induced downregulation of TGR5 and glucose usage deficits. Our results further showed that INT-777 suppressed neuronal apoptosis and improved neurogenesis which were involved in tau phosphorylation and CREB-BDNF signaling. Moreover, INT-777 increased action potential firing of excitatory pyramidal neurons in the hippocampal CA3 and medial prefrontal cortex of ICV-STZ groups. Taken together, these findings reveal that activation of TGR5 has a neuroprotective effect against STZ-induced cognitive impairment by modulating apoptosis, neurogenesis, and neuronal firing in the brain and TGR5 might be a novel and potential target for Alzheimer's disease.

A subpopulation of cortical VIP-expressing interneurons with highly dynamic spines

Structural synaptic plasticity may underlie experience and learning-dependent changes in cortical circuits. In contrast to excitatory pyramidal neurons, insight into the structural plasticity of inhibitory neurons remains limited. Interneurons are divided into various subclasses, each with specialized functions in cortical circuits. Further knowledge of subclass-specific structural plasticity of interneurons is crucial to gaining a complete mechanistic understanding of their contribution to cortical plasticity overall. Here, we describe a subpopulation of superficial cortical multipolar interneurons expressing vasoactive intestinal peptide (VIP) with high spine densities on their dendrites located in layer (L) 1, and with the electrophysiological characteristics of bursting cells. Using longitudinal imaging in vivo, we found that the majority of the spines are highly dynamic, displaying lifetimes considerably shorter than that of spines on pyramidal neurons. Using correlative light and electron microscopy, we confirmed that these VIP spines are sites of excitatory synaptic contacts, and are morphologically distinct from other spines in L1.

KNa1.1 gain-of-function preferentially dampens excitability of murine parvalbumin-positive interneurons

KCNT1 encodes the sodium-activated potassium channel KNa1.1, expressed preferentially in the frontal cortex, hippocampus, cerebellum, and brainstem. Pathogenic missense variants in KCNT1 are associated with intractable epilepsy, namely epilepsy of infancy with migrating focal seizures (EIMFS), and sleep-related hypermotor epilepsy (SHE). In vitro studies of pathogenic KCNT1 variants support predominantly a gain-of-function molecular mechanism, but how these variants behave in a neuron or ultimately drive formation of an epileptogenic circuit is an important and timely question. Using CRISPR/Cas9 gene editing, we introduced a gain-of-function variant into the endogenous mouse Kcnt1 gene. Compared to wild-type (WT) littermates, heterozygous and homozygous knock-in mice displayed greater seizure susceptibility to the chemoconvulsants kainate and pentylenetetrazole (PTZ), but not to flurothyl. Using acute slice electrophysiology in heterozygous and homozygous Kcnt1 knock-in and WT littermates, we demonstrated that CA1 hippocampal pyramidal neurons exhibit greater amplitude of miniature inhibitory postsynaptic currents in mutant mice with no difference in frequency, suggesting greater inhibitory tone associated with the Kcnt1 mutation. To address alterations in GABAergic signaling, we bred Kcnt1 knock-in mice to a parvalbumin-tdTomato reporter line, and found that parvalbumin-expressing (PV+) interneurons failed to fire repetitively with large amplitude current injections and were more prone to depolarization block. These alterations in firing can be recapitulated by direct application of the KNa1.1 channel activator loxapine in WT but are occluded in knock-in littermates, supporting a direct channel gain-of-function mechanism. Taken together, these results suggest that KNa1.1 gain-of-function dampens interneuron excitability to a greater extent than it impacts pyramidal neuron excitability, driving seizure susceptibility in a mouse model of KCNT1-associated epilepsy.

Functional Investigation of a Neuronal Microcircuit in the CA1 Area of the Hippocampus Reveals Synaptic Dysfunction in Dravet Syndrome Mice.

Dravet syndrome is severe childhood-onset epilepsy, caused by loss of function mutations in the SCN1A gene, encoding for the voltage-gated sodium channel NaV1.1. The leading hypothesis is that Dravet is caused by selective reduction in the excitability of inhibitory neurons, due to hampered activity of NaV1.1 channels in these cells. However, these initial neuronal changes can lead to further network alterations. Here, focusing on the CA1 microcircuit in hippocampal brain slices of Dravet syndrome (DS, Scn1aA1783V/WT) and wild-type (WT) mice, we examined the functional response to the application of Hm1a, a specific NaV1.1 activator, in CA1 stratum-oriens (SO) interneurons and CA1 pyramidal excitatory neurons. DS SO interneurons demonstrated reduced firing and depolarized threshold for action potential (AP), indicating impaired activity. Nevertheless, Hm1a induced a similar AP threshold hyperpolarization in WT and DS interneurons. Conversely, a smaller effect of Hm1a was observed in CA1 pyramidal neurons of DS mice. In these excitatory cells, Hm1a application resulted in WT-specific AP threshold hyperpolarization and increased firing probability, with no effect on DS neurons. Additionally, when the firing of SO interneurons was triggered by CA3 stimulation and relayed via activation of CA1 excitatory neurons, the firing probability was similar in WT and DS interneurons, also featuring a comparable increase in the firing probability following Hm1a application. Interestingly, a similar functional response to Hm1a was observed in a second DS mouse model, harboring the nonsense Scn1aR613X mutation. Furthermore, we show homeostatic synaptic alterations in both CA1 pyramidal neurons and SO interneurons, consistent with reduced excitation and inhibition onto CA1 pyramidal neurons and increased release probability in the CA1-SO synapse. Together, these results suggest global neuronal alterations within the CA1 microcircuit extending beyond the direct impact of NaV1.1 dysfunction.

Adolescent Stress Confers Resilience to Traumatic Stress Later in Life: Role of the Prefrontal Cortex

BackgroundAdolescent brains are sensitive to stressors. However, under certain circumstances, developmental stress can promote an adaptive phenotype, allowing individuals to cope better with adverse situations in adulthood, thereby contributing to resilience. MethodsSprague Dawley rats (50 males, 48 females) were subjected to adolescent chronic variable stress (adol CVS) for 2 weeks at postnatal day 45. At postnatal day 85, a group was subjected to single prolonged stress (SPS). After a week, animals were evaluated in an auditory-cued fear conditioning paradigm, and neuronal recruitment during reinstatement was assessed by Fos expression. Patch clamp electrophysiology (17–35 cells/group) was performed in male rats to examine physiological changes associated with resilience. ResultsAdol CVS blocked fear potentiation evoked by SPS. We observed that SPS impaired extinction (males) and enhanced reinstatement (both sexes) of the conditioned freezing response. Prior adol CVS prevented both effects. SPS effects were associated with a reduction of infralimbic (IL) cortex neuronal recruitment after reinstatement in males and increased engagement of the central amygdala in females, both also prevented by adol CVS, suggesting different neurocircuits involved in generating resilience between sexes. We explored the mechanism behind reduced IL recruitment in males by studying the intrinsic excitability of IL pyramidal neurons. SPS reduced excitability of IL neurons, and prior adol CVS prevented this effect. ConclusionsOur data indicate that adolescent stress can impart resilience to the effects of traumatic stress on neuroplasticity and behavior. Our data provide a mechanistic link behind developmental stress-induced behavioral resilience and prefrontal (IL) cortical excitability in males.

Selective impairment of circuits between prefrontal cortex glutamatergic neurons and basal forebrain cholinergic neurons in a tauopathy mouse model.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder linked to cognitive decline. To understand how specific neuronal circuits are impaired in AD, we have used optogenetic and electrophysiological approaches to reveal the functional changes between prefrontal cortex (PFC) and basal forebrain (BF), 2 key regions controlling cognitive processes, in a tauopathy mouse model. We found that the glutamatergic synaptic responses in BF cholinergic neurons from P301S Tau mice (6-8months old) were markedly diminished. The attenuated long-range PFC to BF pathway in the AD model significantly increased the failure rate of action potential firing of BF cholinergic neurons triggered by optogenetic stimulations of glutamatergic terminals from PFC. In contrast, the projection from PFC to other regions, such as amygdala and striatum, was largely unaltered. On the other hand, optogenetic stimulation of cholinergic terminals from BF induced a persistent reduction of the excitability of PFC pyramidal neurons from Tau mice, instead of the transient reduction exhibited in wild-type mice. Taken together, these data have revealed a selective aberration of the pathway between PFC pyramidal neurons and BF cholinergic neurons in a tauopathy mouse model. This circuit deficit may underlie the loss of attention and executive function in AD.

NBI-921352, a first-in-class, NaV1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC500.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for NaV1.1, 134 X for NaV1.2, 276 X for NaV1.7, and >583 Xfor NaV1.3, NaV1.4, and NaV1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.

In vivo electrophysiological study of the targeting of 5-HT3 receptor-expressing cortical interneurons by the multimodal antidepressant, vortioxetine.

The antidepressant vortioxetine has high affinity for the ionotropic 5‐HT3 receptor (5‐HT3R) as well as other targets including the 5‐HT transporter. The procognitive effects of vortioxetine have been linked to altered excitatory:inhibitory balance in cortex. Thus, vortioxetine purportedly inhibits cortical 5‐HT3R‐expressing interneurons (5‐HT3R‐INs) to disinhibit excitatory pyramidal neurons. The current study determined for the first time the effect of vortioxetine on the in vivo firing of putative 5‐HT3R‐INs whilst simultaneously recording pyramidal neuron activity using cortical slow‐wave oscillations as a readout. Extracellular single unit and local field potential recordings were made in superficial layers of the prefrontal cortex of urethane‐anaesthetised rats. 5‐HT3R‐INs were identified by a short‐latency excitation evoked by electrical stimulation of the dorsal raphe nucleus (DRN). Juxtacellular‐labelling found such neurons had the morphological and immunohistochemical properties of 5‐HT3R‐INs: basket cell or bipolar cell morphology, expression of 5‐HT3R‐IN markers and parvalbumin‐immunonegative. Vortioxetine inhibited the short‐latency DRN‐evoked excitation of 5‐HT3R‐INs and simultaneously decreased cortical slow wave oscillations, indicative of pyramidal neuron activation. Likewise, the 5‐HT3R antagonist ondansetron inhibited the short‐latency DRN‐evoked excitation of 5‐HT3R‐INs. However unlike vortioxetine, ondansetron did not decrease cortical slow‐wave oscillations, suggesting a dissociation between this effect and inhibition of 5‐HT3R‐INs. The 5‐HT reuptake inhibitor escitalopram had no consistent effect on any electrophysiological parameter measured. Overall, the current findings suggest that vortioxetine simultaneously inhibits (DRN‐evoked) 5‐HT3R‐INs and excites pyramidal neurons, thereby changing the excitatory:inhibitory balance in cortex. However, under the current experimental conditions, these two effects were dissociable with only the former likely involving a 5‐HT3R‐mediated mechanism.

VIP-Expressing GABAergic Neurons: Disinhibitory vs. Inhibitory Motif and Its Role in Communication Across Neocortical Areas.

GABAergic neurons play a crucial role in shaping cortical activity. Even though GABAergic neurons constitute a small fraction of cortical neurons, their peculiar morphology and functional properties make them an intriguing and challenging task to study. Here, we review the basic anatomical features, the circuit properties, and the possible role in the relevant behavioral task of a subclass of GABAergic neurons that express vasoactive intestinal polypeptide (VIP). These studies were performed using transgenic mice in which the VIP-expressing neurons can be recognized using fluorescent proteins and optogenetic manipulation to control (or regulate) their electrical activity. Cortical VIP-expressing neurons are more abundant in superficial cortical layers than other cortical layers, where they are mainly studied. Optogenetic and paired recordings performed in ex vivo cortical preparations show that VIP-expressing neurons mainly exert their inhibitory effect onto somatostatin-expressing (SOM) inhibitory neurons, leading to a disinhibitory effect onto excitatory pyramidal neurons. However, this subclass of GABAergic neurons also releases neurotransmitters onto other GABAergic and non-GABAergic neurons, suggesting other possible circuit roles than a disinhibitory effect. The heterogeneity of VIP-expressing neurons also suggests their involvement and recruitment during different functions via the inhibition/disinhibition of GABAergic and non-GABAergic neurons locally and distally, depending on the specific local circuit in which they are embedded, with potential effects on the behavioral states of the animal. Although VIP-expressing neurons represent only a tiny fraction of GABAergic inhibitory neurons in the cortex, these neurons’ selective activation/inactivation could produce a relevant behavioral effect in the animal. Regardless of the increasing finding and discoveries on this subclass of GABAergic neurons, there is still a lot of missing information, and more studies should be done to unveil their role at the circuit and behavior level in different cortical layers and across different neocortical areas.