Light-Activated Agonist-Potentiator of GABA Receptors for Reversible Neuroinhibition in Wildtype Mice.

Gamma aminobutyric acid type A receptors (GABARs) play a key role in the mammalian central nervous system (CNS) as drivers of neuroinhibitory circuits, which are commonly targeted for therapeutic purposes with potentiator drugs. However, due to their widespread expression and strong inhibitory action, systemic pharmaceutical potentiation of GABARs inevitably causes adverse effects regardless of the drug selectivity. Therefore, therapeutic guidelines must often limit or exclude clinically available GABAR potentiators, despite their high efficacy, good biodistribution, and favorable molecular properties.

A role for leucine-rich, glioma inactivated 1 in regulating pain sensitivity.

Neuronal hyperexcitability is a key driver of persistent pain states including neuropathic pain. Leucine-rich, glioma inactivated 1 (LGI1), is a secreted protein known to regulate excitability within the nervous system and is the target of autoantibodies from neuropathic pain patients. Therapies that block or reduce antibody levels are effective at relieving pain in these patients, suggesting that LGI1 has an important role in clinical pain.

γ1 GABA Receptors in Spinal Nociceptive Circuits.

GABAergic neurons and GABA receptors (GABARs) are critical elements of almost all neuronal circuits. Most GABARs of the CNS are heteropentameric ion channels composed of two α, two β, and one γ subunits. These receptors serve as important drug targets for benzodiazepine (BDZ) site agonists, which potentiate the action of GABA at GABARs.

The Swiss National MD-PhD Grants Programme: an analysis of the career trajectories of grant recipients between 1992 and 2021.

Aim Of The Study: The aim of this study is to provide an analysis of the career trajectory of the recipients of a Swiss National MD-PhD grant thirty years after the creation of the Swiss interuniversity MD-PhD programme.

Methods: The study surveyed 277 recipients of a Swiss National MD-PhD grant using an online questionnaire in April 2022. There were twenty questions about participants' demographics, the duration of their MD-PhD training, their career trajectory, current position, research and clinical activity, the impact of the support on the recipients' careers, and their satisfaction with various aspects of the grant.

A phospho-deficient α3 glycine receptor mutation alters synaptic glycine and GABA release in mouse spinal dorsal horn neurons.

Glycine receptors (GlyRs), together with GABA receptors, mediate postsynaptic inhibition in most spinal cord and hindbrain neurons. In several CNS regions, GlyRs are also expressed in presynaptic terminals. Here, we analysed the effects of a phospho-deficient mutation (S346A) in GlyR α3 subunits on inhibitory synaptic transmission in superficial spinal dorsal horn neurons, where this subunit is abundantly expressed.

Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord.

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells.

Calretinin-expressing islet cells: a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord.

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells.

Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABA Receptors without Affecting Synaptic Plasticity.

Neurosteroids and benzodiazepines are modulators of the GABA receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP).

c-Maf-positive spinal cord neurons are critical elements of a dorsal horn circuit for mechanical hypersensitivity in neuropathy.

Corticospinal tract (CST) neurons innervate the deep spinal dorsal horn to sustain chronic neuropathic pain. The majority of neurons targeted by the CST are interneurons expressing the transcription factor c-Maf. Here, we used intersectional genetics to decipher the function of these neurons in dorsal horn sensory circuits.

Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn.

Spinally projecting serotonergic neurons play a key role in controlling pain sensitivity and can either increase or decrease nociception depending on physiological context. It is currently unknown how serotonergic neurons mediate these opposing effects. Utilizing virus-based strategies and Tph2-Cre transgenic mice, we identified two anatomically separated populations of serotonergic hindbrain neurons located in the lateral paragigantocellularis (LPGi) and the medial hindbrain, which respectively innervate the superficial and deep spinal dorsal horn and have contrasting effects on sensory perception.

Inhibitory Kcnip2 neurons of the spinal dorsal horn control behavioral sensitivity to environmental cold.

Proper sensing of ambient temperature is of utmost importance for the survival of euthermic animals, including humans. While considerable progress has been made in our understanding of temperature sensors and transduction mechanisms, the higher-order neural circuits processing such information are still only incompletely understood. Using intersectional genetics in combination with circuit tracing and functional neuron manipulation, we identified Kcnip2-expressing inhibitory (Kcnip2) interneurons of the mouse spinal dorsal horn as critical elements of a neural circuit that tunes sensitivity to cold.

Sodium-calcium exchanger-3 regulates pain "wind-up": From human psychophysics to spinal mechanisms.

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is "wind-up," in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3).

Targeting the interaction of GABA receptors with CaMKII with an interfering peptide restores receptor expression after cerebral ischemia and inhibits progressive neuronal death in mouse brain cells and slices.

Cerebral ischemia is the leading cause for long-term disability and mortality in adults due to massive neuronal death. Currently, there is no pharmacological treatment available to limit progressive neuronal death after stroke. A major mechanism causing ischemia-induced neuronal death is the excessive release of glutamate and the associated overexcitation of neurons (excitotoxicity).

Structural MRI Reveals Cervical Spinal Cord Atrophy in the P301L Mouse Model of Tauopathy: Gender and Transgene-Dosing Effects.

In primary tauopathies, the deposition of tau neurofibrillary tangles and threads as well as neurodegenerative changes have been found within the brain and spinal cord. While degenerative changes have been intensively studied in the brain using structural magnetic resonance imaging (MRI), MRI studies investigating the spinal cord are still scarce. In the present study, we acquired high resolution structural MRI of the cervical spinal cord of 8.

Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic.

Glycine receptors (GlyRs) are the primary mediators of fast inhibitory transmission in the mammalian spinal cord, where they modulate sensory and motor signaling. Mutations in GlyR genes as well as some other genes underlie the hereditary disorder hyperekplexia, characterized by episodic muscle stiffness and exaggerated startle responses. Here, we have investigated pain-related behavior and GlyR expression in the spinal cord of the GlyR deficient mutant mouse ().

Midazolam at Low Nanomolar Concentrations Affects Long-term Potentiation and Synaptic Transmission Predominantly via the α1-γ-Aminobutyric Acid Type A Receptor Subunit in Mice.

Background: Midazolam amplifies synaptic inhibition via different γ-aminobutyric acid type A (GABAA) receptor subtypes defined by the presence of α1-, α2-, α3-, or α5-subunits in the channel complex. Midazolam blocks long-term potentiation and produces postoperative amnesia. The aims of this study were to identify the GABAA receptor subtypes targeted by midazolam responsible for affecting CA1 long-term potentiation and synaptic inhibition in neocortical neurons.

Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO).

Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown.

Expression of immunoglobulin constant domain genes in neurons of the mouse central nervous system.

General consensus states that immunoglobulins are exclusively expressed by B lymphocytes to form the first line of defense against common pathogens. Here, we provide compelling evidence for the expression of two heavy chain immunoglobulin genes in subpopulations of neurons in the mouse brain and spinal cord. RNA isolated from excitatory and inhibitory neurons through ribosome affinity purification revealed and transcripts encoding for the constant (Fc), but not the variable regions of IgG3 and IgM.

Morphological and neurochemical characterization of glycinergic neurons in laminae I-IV of the mouse spinal dorsal horn.

A growing body of experimental evidence shows that glycinergic inhibition plays vital roles in spinal pain processing. In spite of this, however, our knowledge about the morphology, neurochemical characteristics, and synaptic relations of glycinergic neurons in the spinal dorsal horn is very limited. The lack of this knowledge makes our understanding about the specific contribution of glycinergic neurons to spinal pain processing quite vague.

Spinally projecting noradrenergic neurons of the locus coeruleus display resistance to AAV2retro-mediated transduction.

Background: The locus coeruleus (LC) is the principal source of noradrenaline (NA) in the central nervous system. Projection neurons in the ventral portion of the LC project to the spinal cord and are considered the main source of spinal NA. To understand the precise physiology of this pathway, it is important to have tools that allow specific genetic access to these descending projections.

A Glra3 phosphodeficient mouse mutant establishes the critical role of protein kinase A-dependent phosphorylation and inhibition of glycine receptors in spinal inflammatory hyperalgesia.

Glycinergic neurons and glycine receptors (GlyRs) exert a critical control over spinal nociception. Prostaglandin E2 (PGE2), a key inflammatory mediator produced in the spinal cord in response to peripheral inflammation, inhibits a certain subtype of GlyRs (α3GlyR) that is defined by the inclusion of α3 subunits and distinctly expressed in the lamina II of the spinal dorsal horn, ie, at the site where most nociceptive nerve fibers terminate. Previous work has shown that the hyperalgesic effect of spinal PGE2 is lost in mice lacking α3GlyRs and suggested that this phenotype results from the prevention of PGE2-evoked protein kinase A (PKA)-dependent phosphorylation and inhibition of α3GlyRs.

Glycine Receptors in Spinal Nociceptive Control-An Update.

Diminished inhibitory control of spinal nociception is one of the major culprits of chronic pain states. Restoring proper synaptic inhibition is a well-established rational therapeutic approach explored by several pharmaceutical companies. A particular challenge arises from the need for site-specific intervention to avoid deleterious side effects such as sedation, addiction, or impaired motor control, which would arise from wide-range facilitation of inhibition.

Neuron-specific spinal cord translatomes reveal a neuropeptide code for mouse dorsal horn excitatory neurons.

The spinal dorsal horn harbors a sophisticated and heterogeneous network of excitatory and inhibitory neurons that process peripheral signals encoding different sensory modalities. Although it has long been recognized that this network is crucial both for the separation and the integration of sensory signals of different modalities, a systematic unbiased approach to the use of specific neuromodulatory systems is still missing. Here, we have used the translating ribosome affinity purification (TRAP) technique to map the translatomes of excitatory glutamatergic (vGluT2) and inhibitory GABA and/or glycinergic (vGAT or Gad67) neurons of the mouse spinal cord.

The α2/α3GABAA receptor modulator TPA023B alleviates not only the sensory but also the tonic affective component of chronic pain in mice.

Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to pathological pain syndromes of neuropathic or inflammatory origin. Drugs that enhance the activity of dorsal horn α2/α3GABAARs normalize exaggerated nociceptive responses in rodents with neuropathic nerve lesions or peripheral inflammation but lack most of the typical side effects of less specific GABAergic drugs. It is however still unknown whether such drugs also reduce the clinically more relevant conscious perception of pain.