Locomotor-related propriospinal V3 neurons produce primary afferent depolarization and modulate sensory transmission to motoneurons.

When a muscle is stretched, sensory feedback not only causes reflexes but also leads to a depolarization of sensory afferents throughout the spinal cord (primary afferent depolarization, PAD), readying the whole limb for further disturbances. This sensory-evoked PAD is thought to be mediated by a trisynaptic circuit, where sensory input activates first-order excitatory neurons that activate GABAergic neurons that in turn activate GABA receptors on afferents to cause PAD, though the identity of these first-order neurons is unclear. Here, we show that these first-order neurons include propriospinal V3 neurons, as they receive extensive sensory input and in turn innervate GABAergic neurons that cause PAD, because optogenetic activation or inhibition of V3 neurons in mice mimics or inhibits sensory-evoked PAD, respectively.

Mitogen-induced defective mitosis transforms neural progenitor cells.

Background: Chromosome instability (CIN) with recurrent copy number alterations is a feature of many solid tumors, including glioblastoma (GBM), yet the genes that regulate cell division are rarely mutated in cancers. Here, we show that the brain-abundant mitogen, platelet-derived growth factor-A (PDGFA) fails to induce the expression of kinetochore and spindle assembly checkpoint genes leading to defective mitosis in neural progenitor cells (NPCs).

Methods: Using a recently reported in vitro model of the initiation of high-grade gliomas from murine NPCs, we investigated the immediate effects of PDGFA exposure on the nuclear and mitotic phenotypes and patterns of gene and protein expression in NPCs, a putative GBM cell of origin.

GABA facilitates spike propagation through branch points of sensory axons in the spinal cord.

Movement and posture depend on sensory feedback that is regulated by specialized GABAergic neurons (GAD2) that form axo-axonic contacts onto myelinated proprioceptive sensory axons and are thought to be inhibitory. However, we report here that activating GAD2 neurons directly with optogenetics or indirectly by cutaneous stimulation actually facilitates sensory feedback to motor neurons in rodents and humans. GABA receptors located at or near nodes of Ranvier of sensory axons cause this facilitation by preventing spike propagation failure at the many axon branch points, which is otherwise common without GABA.

PARP inhibition suppresses the emergence of temozolomide resistance in a model system.

Introduction: Temozolomide (TMZ) is a life prolonging DNA alkylating agent active against glioblastomas (GBM) in which the O6-methylguanine-DNA methyltransferase (MGMT) gene is silenced by promoter methylation. Unfortunately acquired TMZ resistance severely undermines its clinical efficacy. Using an in vitro model, we tested whether poly (ADP-ribose) polymerase-1 and -2 (PARP) inhibition could suppress the emergence of resistance to enhance the effectiveness of TMZ.

5-HT receptors inhibit the monosynaptic stretch reflex by modulating C-fiber activity.

The monosynaptic stretch reflex (MSR) plays an important role in feedback control of movement and posture but can also lead to unstable oscillations associated with tremor and clonus, especially when increased with spinal cord injury (SCI). To control the MSR and clonus after SCI, we examined how serotonin regulates the MSR in the sacrocaudal spinal cord of rats with and without a chronic spinal transection. In chronic spinal rats, numerous 5-HT receptor agonists, including zolmitriptan, methylergonovine, and 5-HT, inhibited the MSR with a potency highly correlated to their binding affinity to 5-HT receptors and not other 5-HT receptors.

Extrasynaptic αGABA receptors on proprioceptive afferents produce a tonic depolarization that modulates sodium channel function in the rat spinal cord.

Activation of GABA receptors on sensory axons produces a primary afferent depolarization (PAD) that modulates sensory transmission in the spinal cord. While axoaxonic synaptic contacts of GABAergic interneurons onto afferent terminals have been extensively studied, less is known about the function of extrasynaptic GABA receptors on afferents. Thus, we examined extrasynaptic αGABA receptors on low-threshold proprioceptive (group Ia) and cutaneous afferents.

Pericytes impair capillary blood flow and motor function after chronic spinal cord injury.

Blood vessels in the central nervous system (CNS) are controlled by neuronal activity. For example, widespread vessel constriction (vessel tone) is induced by brainstem neurons that release the monoamines serotonin and noradrenaline, and local vessel dilation is induced by glutamatergic neuron activity. Here we examined how vessel tone adapts to the loss of neuron-derived monoamines after spinal cord injury (SCI) in rats.