Efficacy of risankizumab across subgroups in patients with active psoriatic arthritis: a post hoc integrated analysis of the phase 3 KEEPsAKE 1 and KEEPsAKE 2 randomized controlled trials.

In the KEEPsAKE 1 (NCT03675308) and KEEPsAKE 2 (NCT03671148) phase 3 trials, risankizumab demonstrated greater efficacy compared with placebo in patients with active psoriatic arthritis (PsA). This post hoc integrated analysis evaluated achieving the following efficacy outcomes at weeks 24 and 52 by baseline demographics and clinical characteristics: ≥20%/50%/70% improvement in American College of Rheumatology response criteria (ACR20/50/70), ≥90% improvement in Psoriasis Area and Severity Index, minimal disease activity status, Low Disease Activity status (Disease Activity in Psoriatic Arthritis), and minimal clinically important difference in pain. Baseline demographics and clinical characteristics were similar between risankizumab ( = 707) and placebo ( = 700) groups.

Circuit-based interventions in the dentate gyrus rescue epilepsy-associated cognitive dysfunction.

Temporal lobe epilepsy is associated with significant structural pathology in the hippocampus. In the dentate gyrus, the summative effect of these pathologies is massive hyperexcitability in the granule cells, generating both increased seizure susceptibility and cognitive deficits. To date, therapeutic approaches have failed to improve the cognitive symptoms in fully developed, chronic epilepsy.

Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation.

Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exact mechanistic link between these two AD lesions remains enigmatic. Through injection of human AD-brain-derived pathological tau (AD-tau) into Aβ plaque-bearing mouse models that do not overexpress tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) and neuropil threads (NTs).

Loss of CDKL5 in Glutamatergic Neurons Disrupts Hippocampal Microcircuitry and Leads to Memory Impairment in Mice.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency is a neurodevelopmental disorder characterized by epileptic seizures, severe intellectual disability, and autistic features. Mice lacking CDKL5 display multiple behavioral abnormalities reminiscent of the disorder, but the cellular origins of these phenotypes remain unclear. Here, we find that ablating CDKL5 expression specifically from forebrain glutamatergic neurons impairs hippocampal-dependent memory in male conditional knock-out mice.

Massively augmented hippocampal dentate granule cell activation accompanies epilepsy development.

In a mouse model of temporal lobe epilepsy, multicellular calcium imaging revealed that disease emergence was accompanied by massive amplification in the normally sparse, afferent stimulation-induced activation of hippocampal dentate granule cells. Patch recordings demonstrated reductions in local inhibitory function within the dentate gyrus at time points where sparse activation was compromised. Mimicking changes in inhibitory synaptic function and transmembrane chloride regulation was sufficient to elicit the dentate gyrus circuit collapse evident during epilepsy development.

Engraftment of nonintegrating neural stem cells differentially perturbs cortical activity in a dose-dependent manner.

Neural stem cell (NSC) therapy represents a potentially powerful approach for gene transfer in the diseased central nervous system. However, transplanted primary, embryonic stem cell- and induced pluripotent stem cell-derived NSCs generate largely undifferentiated progeny. Understanding how physiologically immature cells influence host activity is critical to evaluating the therapeutic utility of NSCs.

Protracted postnatal development of sparse, specific dentate granule cell activation in the mouse hippocampus.

The dentate gyrus (DG) is a critical entry point regulating function of the hippocampus. Integral to this role are the sparse, selective activation characteristics of the principal cells of the DG, dentate granule cells (DGCs). This sparse activation is important both in cognitive processing and in regulation of pathological activity in disease states.

Deterministic and stochastic neuronal contributions to distinct synchronous CA3 network bursts.

Computational studies have suggested that stochastic, deterministic, and mixed processes all could be possible determinants of spontaneous, synchronous network bursts. In the present study, using multicellular calcium imaging coupled with fast confocal microscopy, we describe neuronal behavior underlying spontaneous network bursts in developing rat and mouse hippocampal area CA3 networks. Two primary burst types were studied: giant depolarizing potentials (GDPs) and spontaneous interictal bursts recorded in bicuculline, a GABA(A) receptor antagonist.

Hippocampal microcircuit dynamics probed using optical imaging approaches.

Mammalian cortical structures are endowed with the capacity for plasticity, which emerges from a combination of the dynamics of circuit connectivity and function, and the intrinsic function of the neurons within the circuit. However, this capacity is accompanied by a significant risk: the capability to generate seizure discharges is also a property of all mammalian cortices. How do cortical circuits reconcile the requirement to maintain plasticity, but at the same time control seizure initiation? These issues come into particular focus in the hippocampus.

An increase in persistent sodium current contributes to intrinsic neuronal bursting after status epilepticus.

Brain damage causes multiple changes in synaptic function and intrinsic properties of surviving neurons, leading to the development of chronic epilepsy. In the widely used pilocarpine-status epilepticus (SE) rat model of temporal lobe epilepsy (TLE), a major alteration is the marked increase in the fraction of intrinsically bursting CA1 pyramidal cells. Here we have differentiated between two types of bursting phenotypes: 1) bursting in response to threshold-straddling excitatory current pulses (low-threshold bursting) and 2) bursting only in response to suprathreshold stimuli (high-threshold bursting).

Selective induction of astrocytic gliosis generates deficits in neuronal inhibition.

Reactive astrocytosis develops in many neurologic diseases, including epilepsy. Astrocytotic contributions to pathophysiology are poorly understood. Studies examining this are confounded by comorbidities accompanying reactive astrocytosis.

Recruitment of apical dendritic T-type Ca2+ channels by backpropagating spikes underlies de novo intrinsic bursting in hippocampal epileptogenesis.

A single episode of status epilepticus (SE) induced in rodents by the convulsant pilocarpine, produces, after a latent period of > or = 2 weeks, a chronic epileptic condition. During the latent period of epileptogenesis, most CA1 pyramidal cells that normally fire in a regular pattern, acquire low-threshold bursting behaviour, generating high-frequency clusters of 3-5 spikes as their minimal response to depolarizing stimuli. Recruitment of a Ni(2+)- and amiloride-sensitive T-type Ca(2+) current (I(CaT)), shown to be up-regulated after SE, plays a critical role in burst generation in most cases.

Pre- and postsynaptic activation of M-channels by a novel opener dampens neuronal firing and transmitter release.

The M-type K(+) current (M-current), encoded by Kv7.2/3 (KCNQ2/3) K(+) channels, plays a critical role in regulating neuronal excitability because it counteracts subthreshold depolarizations. Here we have characterized the functions of pre- and postsynaptic M-channels using a novel Kv7.

Contribution of persistent Na+ current and M-type K+ current to somatic bursting in CA1 pyramidal cells: combined experimental and modeling study.

The intrinsic firing modes of adult CA1 pyramidal cells vary along a continuum of "burstiness" from regular firing to rhythmic bursting, depending on the ionic composition of the extracellular milieu. Burstiness is low in neurons exposed to a normal extracellular Ca(2+) concentration ([Ca(2+)](o)), but is markedly enhanced by lowering [Ca(2+)](o), although not by blocking Ca(2+) and Ca(2+)-activated K(+) currents. We show, using intracellular recordings, that burstiness in low [Ca(2+)](o) persists even after truncating the apical dendrites, suggesting that bursts are generated by an interplay of membrane currents at or near the soma.

Axo-somatic and apical dendritic Kv7/M channels differentially regulate the intrinsic excitability of adult rat CA1 pyramidal cells.

Kv7/KCNQ/M channel subunits are widely expressed in peripheral and central neurons, where they give rise to a muscarinic-sensitive, subthreshold, and noninactivating K+ current (M current). Immunohistochemical data suggest that Kv7/M channels are expressed in both axons, somata and dendrites, but their distinctive roles in these compartments are not known. Here we used intracellular microelectrode recordings to monitor the effects of selective Kv7/M channel modulators focally applied to the axo-somatic region and to the apical dendrites of adult rat CA1 pyramidal cells.

Proximal persistent Na+ channels drive spike afterdepolarizations and associated bursting in adult CA1 pyramidal cells.

In many principal brain neurons, the fast, all-or-none Na+ spike initiated at the proximal axon is followed by a slow, graded after depolarization (ADP). The spike ADP is critically important in determining the firing mode of many neurons; large ADPs cause neurons to fire bursts of spikes rather than solitary spikes. Nonetheless, not much is known about how and where spike ADPs are initiated.

A transitional period of Ca2+-dependent spike afterdepolarization and bursting in developing rat CA1 pyramidal cells.

During postnatal development neurones display discharge behaviours that are not present in the adult, yet they are essential for the normal maturation of the nervous system. Neonatal CA1 pyramidal cells, like their adult counterparts, fire regularly, but excitatory GABAergic transmission drives them to generate spontaneous high-frequency bursts until postnatal day (P) 15. Using intracellular recordings in hippocampal slices from rats at P8 to P25, we show herein that as the network-driven burst activity fades out, most CA1 pyramidal cells become intrinsically bursting neurones.

KCNQ/M channels control spike afterdepolarization and burst generation in hippocampal neurons.

KCNQ channel subunits are widely expressed in peripheral and central neurons, where they give rise to a muscarinic-sensitive, subthreshold, and noninactivating K+ current (M-current). It is generally agreed that activation of KCNQ/M channels contributes to spike frequency adaptation during sustained depolarizations but is too slow to influence the repolarization of solitary spikes. This concept, however, is based mainly on experiments with muscarinic agonists, the multiple effects on membrane conductances of which may overshadow the distinctive effects of KCNQ/M channel block.