Inhibition Mediated by Glycinergic and GABAergic Receptors on Excitatory Neurons in Mouse Superficial Dorsal Horn Is Location-Specific but Modified by Inflammation.

The superficial dorsal horn is the synaptic termination site for many peripheral sensory fibers of the somatosensory system. A wide range of sensory modalities are represented by these fibers, including pain, itch, and temperature. Because the involvement of local inhibition in the dorsal horn, specifically that mediated by the inhibitory amino acids GABA and glycine, is so important in signal processing, we investigated regional inhibitory control of excitatory interneurons under control conditions and peripheral inflammation-induced mechanical allodynia.

Transient, activity dependent inhibition of transmitter release from low threshold afferents mediated by GABAA receptors in spinal cord lamina III/IV.

Background: Presynaptic GABAA receptors (GABAARs) located on central terminals of low threshold afferent fibers are thought to be involved in the processing of touch and possibly in the generation of tactile allodynia in chronic pain. These GABAARs mediate primary afferent depolarization (PAD) and modulate transmitter release. The objective of this study was to expand our understanding of the presynaptic inhibitory action of GABA released onto primary afferent central terminals following afferent stimulation.

Molecular substrates of altered axonal growth and brain connectivity in a mouse model of schizophrenia.

22q11.2 deletion carriers show specific cognitive deficits, and ∼30% of them develop schizophrenia. One of the disrupted genes is ZDHHC8, which encodes for a palmitoyltransferase.

Synaptic GluN2A and GluN2B containing NMDA receptors within the superficial dorsal horn activated following primary afferent stimulation.

NMDA receptors are important elements in pain signaling in the spinal cord dorsal horn. They are heterotetramers, typically composed of two GluN1 and two of four GluN2 subunits: GluN2A-2D. Mice lacking some of the GluN2 subunits show deficits in pain transmission yet functional synaptic localization of these receptor subtypes in the dorsal horn has not been fully resolved.

Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn.

Cutaneous mechanosensory neurons detect mechanical stimuli that generate touch and pain sensation. Although opioids are generally associated only with the control of pain, here we report that the opioid system in fact broadly regulates cutaneous mechanosensation, including touch. This function is predominantly subserved by the delta opioid receptor (DOR), which is expressed by myelinated mechanoreceptors that form Meissner corpuscles, Merkel cell-neurite complexes, and circumferential hair follicle endings.

The pattern of cortical dysfunction in a mouse model of a schizophrenia-related microdeletion.

We used a mouse model of the schizophrenia-predisposing 22q11.2 microdeletion to evaluate how this genetic lesion affects cortical neural circuits at the synaptic, cellular, and molecular levels. Guided by cognitive deficits, we demonstrated that mutant mice display robust deficits in high-frequency synaptic transmission and short-term plasticity (synaptic depression and potentiation), as well as alterations in long-term plasticity and dendritic spine stability.

Pre- and postsynaptic inhibitory control in the spinal cord dorsal horn.

Sensory information transmitted to the spinal cord dorsal horn is modulated by a complex network of excitatory and inhibitory interneurons. The two main inhibitory transmitters, GABA and glycine, control the flow of sensory information mainly by regulating the excitability of dorsal horn neurons. A presynaptic action of GABA has also been proposed as an important modulatory mechanism of transmitter release from sensory primary afferent terminals.

Maturation of spinal motor neurons derived from human embryonic stem cells.

Our understanding of motor neuron biology in humans is derived mainly from investigation of human postmortem tissue and more indirectly from live animal models such as rodents. Thus generation of motor neurons from human embryonic stem cells and human induced pluripotent stem cells is an important new approach to model motor neuron function. To be useful models of human motor neuron function, cells generated in vitro should develop mature properties that are the hallmarks of motor neurons in vivo such as elaborated neuronal processes and mature electrophysiological characteristics.

Evidence for altered hippocampal function in a mouse model of the human 22q11.2 microdeletion.

22q11.2 chromosomal deletions are recurrent copy number mutations that increase the risk of schizophrenia around thirty-fold. Deletion of the orthologous chromosomal region in mice offers an opportunity to characterize changes to neuronal structure and function that may account for the development of this disease.

Modulation of neurite outgrowth by activation of calcium-permeable kainate receptors expressed by rat nociceptive-like dorsal root ganglion neurons.

Neurite outgrowth is a fundamental step in establishing proper neuronal connections in the developing central nervous system. Dynamic control of outgrowth has been attributed to changes in growth cone Ca2+ levels in response to extracellular cues. Here we have investigated a possible role for Ca2+ permeable kainate (KA) receptors in regulating neurite outgrowth of nociceptive-like dorsal root ganglion (DRG) neurons.

Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type (AMPA-type) glutamate receptors (AMPARs) play an important role in plasticity at central synapses. Although there is anatomical evidence for AMPAR expression in the peripheral nervous system, the functional role of such receptors in vivo is not clear. To address this issue, we generated mice specifically lacking either of the key AMPAR subunits, GluA1 or GluA2, in peripheral, pain-sensing neurons (nociceptors), while preserving expression of these subunits in the central nervous system.

A functionally characterized test set of human induced pluripotent stem cells.

Human induced pluripotent stem cells (iPSCs) present exciting opportunities for studying development and for in vitro disease modeling. However, reported variability in the behavior of iPSCs has called their utility into question. We established a test set of 16 iPSC lines from seven individuals of varying age, sex and health status, and extensively characterized the lines with respect to pluripotency and the ability to terminally differentiate.

Synaptic pathways and inhibitory gates in the spinal cord dorsal horn.

Disinhibition in the dorsal horn accompanies peripheral nerve injury and causes the development of hypersensitivity to mild stimuli. This demonstrates the critical importance of inhibition in the dorsal horn for maintaining normal sensory signaling. Here we show that disinhibition induces a novel polysynaptic low-threshold input onto lamina I output neurons, suggesting that inhibition normally suppresses a preexisting pathway that probably contributes to abnormal pain sensations such as allodynia.

Glycinergic and GABAergic tonic inhibition fine tune inhibitory control in regionally distinct subpopulations of dorsal horn neurons.

Inhibition mediated by glycine and GABA in the spinal cord dorsal horn is essential for controlling sensitivity to painful stimuli. Loss of inhibition results in hyperalgesia, a sensitized response to a painful stimulus, and allodynia, a pain-like response to an innocuous stimulus like touch. The latter is due, in part, to disinhibition of an excitatory polysynaptic pathway linking low threshold touch input to pain projection neurons.

NR2 subunits and NMDA receptors on lamina II inhibitory and excitatory interneurons of the mouse dorsal horn.

Background: NMDA receptors expressed by spinal cord neurons in the superficial dorsal horn are involved in the development of chronic pain associated with inflammation and nerve injury. The superficial dorsal horn has a complex and still poorly understood circuitry that is mainly populated by inhibitory and excitatory interneurons. Little is known about how NMDA receptor subunit composition, and therefore pharmacology and voltage dependence, varies with neuronal cell type.

An in vitro assay system for studying synapse formation between nociceptive dorsal root ganglion and dorsal horn neurons.

Synapses between nociceptive dorsal root ganglion (DRG) neurons and spinal cord dorsal horn neurons represent the first loci for transmission of painful stimuli. Our knowledge of the molecular organization and development of these synapses is sparse due, partly, to a lack of a reliable model system that reconstitutes synaptogenesis between these two neuronal populations. To address this issue, we have established an in vitro assay system consisting of separately purified DRG neurons and dorsal horn neurons on astrocyte microislands.

Low-threshold primary afferent drive onto GABAergic interneurons in the superficial dorsal horn of the mouse.

Inhibition in the spinal cord dorsal horn is crucial for maintaining separation of touch and pain modalities. Disruption of this inhibition results in allodynia, allowing low-threshold drive onto pain and temperature-sensitive projection neurons. This low-threshold (LT) excitatory pathway is normally under strong inhibition.