Biology subjects

Gorassini, M. A.

Publications and source records attributed to Gorassini, M. A..

4 recordsLinked to original sources

bioRxiv2026

Reduced GABAB receptor activation and post activation depression of proprioceptive afferents after spinal cord injury.

Despite a long history of studying presynaptic inhibition of the Ia afferent synapse that produces the monosynaptic EPSP on motoneurons, recent evidence has upset the conventional idea that GABAA receptors mediate this inhibition and instead suggests that there are mainly GABAB receptors at this synapse. However, without targeted access to the GABAergic neurons that activate these receptors, quantifying their functional contribution to presynaptic inhibition has proven difficult. We demonstrate here that focal optogenetic activation of terminals of a subpopulation of GAD2+ GABAergic neurons that exclusively project ventrally to Ia afferent synapses produce long-lasting presynaptic inhibition that is entirely mediated by GABAB receptors and simultaneously produces a characteristic brief GABAA receptor-mediated IPSP on the motoneurons. These ventral GAD2 neurons are recurrently activated by Ia afferents, contributing to post-activation depression with repeated afferent reflex testing, with a similar long time-course to post-activation depression of the H-reflex induced in humans from either repetitive activation of the same Ia afferents or from antagonist nerve conditioning. In contrast, focal activation of dorsally projecting GAD2 neurons does not directly cause presynaptic inhibition or postsynaptic IPSPs but does produce primary afferent depolarization. Following chronic spinal cord injury (SCI), the expression of GABAB receptors on the Ia terminal is halved, and in mice and humans, is associated with a similar decrease of GABAB receptor-mediated post-activation depression of Ia-EPSPs transmission, which is reversed by the GABAB receptor agonist baclofen. In summary, GABAB receptors mediate presynaptic inhibition, but are down regulated with SCI, contributing to reflex hyperexcitability associated with spasticity. Key Points SummaryO_LIPresynaptic inhibition of Ia afferents is mediated by the recurrent activation of terminal GABAB receptors by a subpopulation of ventrally projecting GAD2+ interneurons. C_LIO_LIIn contrast, dorsally projecting GAD2+ interneurons activate GABAA receptors on Ia afferent nodes to facilitate action potential conduction through branchpoints. C_LIO_LIRepetitive activation of Ia afferents at rates of every 10 s or faster produces post-activation depression via neurotransmitter depletion and from activation of terminal GABAB receptors. C_LIO_LIThese ventrally projecting GAD2+ interneurons can also be activated by other afferents that then produce PAD-evoked spikes to produce post-activation depression from conditioning nerve stimulation. C_LIO_LIThe reduction of GABAB receptors on the Ia terminal in spinal cord injury results in reduced presynaptic inhibition and post-activation depression, contributing to reflex hyperexcitability. C_LI O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/700955v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@17abd51org.highwire.dtl.DTLVardef@12316baorg.highwire.dtl.DTLVardef@a92168org.highwire.dtl.DTLVardef@1d06ca0_HPS_FORMAT_FIGEXP M_FIG Abstract legend: Schematic of GABAergic circuit producing presynaptic inhibition and primary afferent depolarization (PAD) in proprioceptive Ia afferents. We propose two populations of GAD2+ GABAergic interneurons, one with dorsal projections (purple) that activate GABAA receptors on the nodes of Ia afferents to produce PAD and subsequent facilitation of Ia afferent conduction, and another ventrally projecting population (pink) that activates GABAB receptors on the Ia afferent terminal to produce presynaptic inhibition via inhibition of VCa2+ channels and reduction of neurotransmitter release and replenishment. Both are activated by first order interneurons (grey). Repetitive activation of Ia afferents (green extensor) recurrently activates twhe ventrally projecting GAD2+ neurons to activate terminal GABAB receptors and long-lasting post-activation depression of Ia EPSPs and reflexes as measured from ventral root recordings. Strong conditioning stimulation of other afferents (blue flexor) activates dorsal GAD2+ neurons that can produce PAD-evoked spikes in extensor afferents that orthodromically activate motoneurons to set up post-activation depression of subsequent extensor reflexes. Here, PAD is also evoked in other afferents (flexor) by dorsally projecting GAD2+ neurons (light pink branch) but without activation of the ventrally projecting GAD2+ neurons or presynaptic inhibition. C_FIG

neuroscience↗

bioRxiv2021

Facilitation of sensory axon conduction to motoneurons during cortical or sensory evoked primary afferent depolarization (PAD) in humans

Sensory and corticospinal (CST) pathways activate spinal GABAergic interneurons with axo-axonic connections onto proprioceptive (Ia) afferents that depolarize these afferents (termed primary afferent depolarization, PAD). In rodents sensory-evoked PAD is produced by GABAA receptors at nodes of Ranvier in Ia-afferents, rather than at presynaptic terminals, and facilitates action potential propagation to motoneurons by preventing branch point failures, rather than causing presynaptic inhibition. Here we examined if PAD likewise facilitates the Ia-afferent mediated H-reflex in humans by evoking PAD with both sensory and CST stimulation. H-reflexes in several lower limb muscles were facilitated by prior conditioning from low-threshold proprioceptive, cutaneous or CST pathways, with a similar time course ([~]200 ms) to the PAD measured in rodent Ia-afferents. Long trains of repeated cutaneous or proprioceptive afferent stimulation produced long-lasting facilitation of the H-reflex for up to 2 minutes, consistent with the tonic depolarization of rodent Ia-afferents mediated by nodal 5-GABA receptors for similar stimulation trains. Facilitation of the conditioned H-reflexes was not mediated by direct facilitation of the motoneurons because isolated stimulation of sensory or CST pathways did not modulate the firing rate of tonically activated motor units in tested muscles. Furthermore, cutaneous conditioning increased the firing probability of a single motor unit during the H-reflex without increasing its firing rate at this time, indicating that the underlying excitatory postsynaptic potential (EPSP) was more probable, but not larger. These results are consistent with sensory and CST pathways activating nodal GABAA receptors that reduce intermittent failure of action potentials propagating into Ia-afferent branches. Key Points SummaryO_LIThe control of posture and movement requires peripheral sensory feedback, which was previously thought to be inhibited by specialized GABAergic neurons in the spinal cord. C_LIO_LIBased on new findings in rodents, we provide evidence in humans that sensory and corticospinal pathways that likely activate these GABAergic pathways facilitate, rather than inhibit, the flow of sensory feedback in afferents that carry information about body position, movement and effort. C_LIO_LIThese new findings of how sensory and descending pathways facilitate this sensory feedback to spinal motor neurons can now be applied to people with injury to the brain or spinal cord where these GABA neurons are affected, allowing us to understand how altered sensory control may affect residual motor function and the production of involuntary muscle spasticity. C_LI

neuroscience↗

bioRxiv2021

Nodal GABA facilitates axon spike transmission 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, facilitates sensory feedback to motoneurons in awake rodents and humans. GABAA receptors and GAD2+ innervation at or near nodes of Ranvier of sensory axons cause this facilitation, preventing spike propagation failure at the many axon branch points, which is otherwise common without GABA. In contrast, GABAA receptors are generally lacking from axon terminals (unlike GABAB) and do not presynaptically inhibit transmitter release onto motoneurons. GABAergic innervation near nodes and branch points allows individual branches to function autonomously, with GAD2+ neurons regulating which branches conduct, adding a computational layer to the neuronal networks generating movement and likely generalizing to other CNS axons.

neuroscience↗

bioRxiv2019

Altered motoneuron properties and spinal serotonin contribute to motor deficits in a rabbit hypoxia ischemia model of cerebral palsy

Cerebral palsy (CP) is caused by a variety of factors attributed to early brain damage, resulting in permanently impaired motor control, marked by weakness and muscle stiffness. To find out if altered physiology of spinal motoneurons (MNs) could contribute to movement deficits, we performed whole cell patch clamp in neonatal rabbit spinal cord slices after developmental injury at 79% gestation. After preterm hypoxia-ischemia (HI), rabbits are born with motor deficits consistent with a spastic phenotype including hypertonia and hyperreflexia. There is a range in severity, thus kits are classified as severely affected, mildly affected, or unaffected based on modified Ashworth scores and other behavioral tests. At postnatal day (P)0-5, we recorded electrophysiological parameters of 40 MNs in transverse spinal cord slices using whole cell patch clamp. Using a multivariate analysis of neuronal parameters, we found significant differences between groups (severe, mild, unaffected and sham control MNs), age (P0 to P5) and spinal cord region (cervical to sacral). Severe HI MNs showed more sustained firing patterns, depolarized resting membrane potential, and a higher threshold for action potentials. These properties could contribute to both muscle stiffness and weakness, respectively, hallmarks of spastic CP. Interestingly altered persistent inward currents (PICs) and morphology in severe HI MNs would dampen excitability (reduced normalized PIC amplitude and increased dendritic length). In summary, changes we observed in spinal MN physiology likely contribute to severity of the phenotype including weakness and hypertonia, and therapeutic strategies for CP could target excitability of spinal MNs. Key PointsO_LIPhysiology of neonatal spinal motoneurons is altered after in utero hypoxia-ischemic injury C_LIO_LIIn motoneurons from severely affected animals there is more sustained firing (lower {Delta}I values), a depolarized resting potential, but a higher voltage threshold for action potential firing. C_LIO_LIAltered motoneuron excitability could contribute directly to muscle stiffness and spasticity in cerebral palsy. C_LI

neuroscience↗