The Journal of neuroscience : the official journal of the Society for Neuroscience
-
Millions of patients suffer from debilitating spinal cord injury (SCI) without effective treatments. Elevating cAMP promotes CNS neuron growth in the presence of growth-inhibiting molecules. cAMP's effects on neuron growth are partly mediated by Epac, comprising Epac1 and Epac2; the latter predominantly expresses in postnatal neural tissue. Here, we hypothesized that Epac2 activation would enhance axonal outgrowth after SCI. ⋯ Elevating cAMP levels encourages injured CNS neurons to sprout and extend neurites. We have demonstrated that activating its downstream effector, Epac2, enhances neurite outgrowth in vitro, even in the presence of an inhibitory environment. Using a novel biomaterial-based drug delivery system in the form of a hydrogel to achieve local delivery of an Epac2 agonist, we further demonstrated that specific activation of Epac2 enhances axonal outgrowth and minimizes glial activation in an ex vivo model of spinal cord injury, suggesting a new strategy for spinal cord repair.
-
The amplitude of high broadband activity in human cortical field potentials indicates local processing and has repeatedly been shown to reflect motor control in the primary motor cortex. In a group of male and female subjects affected by essential tremor and undergoing deep brain stimulation surgery, ventral intermediate nucleus low-frequency oscillations (<30 Hz) entrain the corticomotor high broadband activity (>40 Hz) during rest, relinquishing that role during movement execution. This finding suggests that there is significant cross-rhythm communication between thalamocortical regions, and motor behavior corresponds to changes in thalamocortical phase-amplitude coupling profiles. ⋯ We show how the low-frequency oscillation from the ventral intermediate nucleus, known as the motor nucleus of the thalamus, entrains the excitability of the primary motor cortex, as reflected by the phase-amplitude coupling between the two regions. We show that thalamocortical phase-amplitude coupling is a manifestation of a gating mechanism for movement execution mediated by the thalamus. These findings highlight the importance of incorporating cross-frequency relationship in models of motor behavior; and given the spatial specificity of this mechanism, this work could be used to improve functional targeting during surgical implantations in subcortical regions.
-
Transient receptor potential melastatin 3 (TRPM3) is a nonselective cation channel that is inhibited by Gβγ subunits liberated following activation of Gαi/o protein-coupled receptors. Here, we demonstrate that TRPM3 channels are also inhibited by Gβγ released from Gαs and Gαq Activation of the Gs-coupled adenosine 2B receptor and the Gq-coupled muscarinic acetylcholine M1 receptor inhibited the activity of TRPM3 heterologously expressed in HEK293 cells. This inhibition was prevented when the Gβγ sink βARK1-ct (C terminus of β-adrenergic receptor kinase-1) was coexpressed with TRPM3. ⋯ Our results demonstrate that activation of Gs- and Gq-coupled GPCRs in recombinant cells and sensory neurons inhibits TRPM3 via Gβγ liberation. We also demonstrated that Gs- and Gq-coupled receptors inhibit TRPM3 in vivo, thereby reducing pain produced by activation of TRPM3, and inflammatory heat hypersensitivity. Our results identify Gβγ inhibition of TRPM3 as an effector mechanism shared by the major Gα subunits.
-
Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-β (Aβ) peptide. Accumulation of Aβ, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression being underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored. ⋯ Using a combination of genetic and pharmacological approaches, we found that the p110δ isoform of phosphoinositide 3-kinase (PI3K) is involved in anterograde trafficking of the amyloid precursor protein in neurons and in the secretion of tumor necrosis factor-alpha from microglial cells. Genetic inactivation of PI3Kδ reduces Aβ plaque deposition and abrogates the inflammatory response, resulting in a complete rescue of the life span and spatial memory performance. We conclude that inhibiting PI3Kδ represents a novel therapeutic approach to ameliorate AD pathology by dampening plaque accumulation and microglial-dependent neuroinflammation.
-
Neonatal tissue injury disrupts the balance between primary afferent-evoked excitation and inhibition onto adult spinal projection neurons. However, whether this reflects cell-type-specific alterations at synapses onto ascending projection neurons, or rather is indicative of global changes in synaptic signaling across the mature superficial dorsal horn (SDH), remains unknown. Therefore the present study investigated the effects of neonatal surgical injury on primary afferent synaptic input to adult mouse SDH interneurons using in vitro patch-clamp techniques. ⋯ Although recent work has demonstrated that early life injury weakens the ability of sensory afferents to evoke feedforward inhibition of adult spinal projection neurons, the underlying circuit mechanisms remain poorly understood. Here we demonstrate that neonatal surgical injury leads to persistent deficits in primary afferent drive to both GABAergic and presumed glutamatergic neurons in the mature superficial dorsal horn (SDH), and modifies activity-dependent plasticity at sensory synapses onto the GABAergic population. The functional denervation of spinal interneurons within the mature SDH may contribute to the "priming" of developing pain pathways following early life injury.