Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.01.21.700955

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

Metz, K.·Hari, K.·Lucas-Osma, A.·Mangukia, R.·Ayantayo, T.·Concha Matos, I.·Sun, Y.·Yang, J. F.·Bennett, D. J.·Gorassini, M. A.
View original source ↗Export metadata ↓

Abstract

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

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Metz, K., Hari, K., Lucas-Osma, A., Mangukia, R., Ayantayo, T., Concha Matos, I., Sun, Y., Yang, J. F., Bennett, D. J., Gorassini, M. A.. 2026-01-22. Reduced GABAB receptor activation and post activation depression of proprioceptive afferents after spinal cord injury.. https://doi.org/10.64898/2026.01.21.700955

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Neurodegeneration-inducing macromolecules exit the brain via nanovascular conduits formed by reticular fibroblasts

Accumulation of proteins such as amyloid beta (Abeta), hyperphosphorylated tau and alpha-synuclein within the brain alters neural information processing and causes neurodegeneration(1-3), but how toxic solutes are cleared from the brain remains highly controversial(4,5). Proposed exit routes include efflux across endothelial cells into the blood(6,7), and movement to the pial surface via vasomotion-induced pumping along spaces within arteriolar smooth muscle(8) or via outflow along the perivascular space of ascending venules promoted by water flux through astrocytes (the glymphatic system(9)). From the pial surface of the brain, drainage may continue to dural lymphatics, along the outer sheaths of exiting cranial nerves and across the cribriform plate(10-14). We now report the presence, in mice and humans, of 2 micron diameter conduits that remove fluorescently labelled tau and Abeta from the brain. These conduits form a spatially-organised mesh within the walls of penetrating arterioles and pial arteries, and around the surface of ascending venules and deep cerebral and pial veins. They course through the pial and arachnoid layers to span the CSF space, wrapping the brain and cranial nerves. They are formed of reticular fibroblasts, which label for VE-cadherin(15) and PDGFRalpha(16), the lymphatic markers(17) podoplanin, VEGFR3 and Prox1, and reticular fibroblast extracellular matrix components collagen I and VI(16,18-20). Parenchymal tau drains from the brain at a similar rate via arteriolar conduits and via conduits around venules, arguing against preferential removal by a glymphatic mechanism. In Alzheimer's disease model mice, Abeta is seen traversing these lymph node-like conduits. Modulation of molecular transfer via this route may accelerate or delay cognitive decline, and slowed transfer from arteriolar to pial-arachnoid conduits may initiate cerebral amyloid angiopathy.

neuroscience↗
bioRxiv2026

Analysis of the influence of gradual changes in matrix sentence similarity on neural envelope tracking

Neural tracking of speech is a well-established phenomenon in neuroscience. However, for speech signals with a fixed structure, significant correlations between speech envelopes and neurophysiological representations occur even for unheard sentences. We exploit a structured speech-in-noise matrix hearing test (Oldenburger Sentence Test, OLSA) to systematically quantify the relationship between acoustic sentence similarity and neural tracking. Simultaneous magnetoencephalography (MEG) and 76-channel electroencephalography (EEG) data, including 16 channels positioned directly around the ears (ear-EEG), were recorded from 21 young adults with normal hearing during the presentation of clean-speech audiobooks and OLSA sentences at six signal-to-noise ratios. A linear decoder trained on audiobooks reconstructed OLSA sentence envelopes. Reconstruction accuracies were compared using a linear mixed model across heard (matched) and unheard (mismatched) sentences of varying acoustic similarity. Significant reconstruction accuracies were achieved across MEG, EEG, and ear-EEG for both matched and mismatched sentences. For mismatched sentences, these accuracies gradually increased with their acoustic similarity to the heard speech data. The high similarity between sentences, which is especially prominent in matrix tests, can cause significant spurious tracking for mismatched stimuli. This effect can reach levels comparable to those of matched sentences and can be mistaken for true neural tracking. Robust neural tracking across modalities further supported the established viability of ear-EEG compared to whole-head systems.

neuroscience↗
bioRxiv2026

Seizures and tauopathy following neurotrauma are mediated by prion protein and metabotropic glutamate receptor 5

Traumatic brain injury (TBI) is one of the world's leading causes of death and disability and a major risk factor for dementias. The primary dementia associated with TBI is chronic traumatic encephalopathy (CTE), a neurodegenerative disease classified as a tauopathy, in which toxic tau molecules lead to disease pathologies and degeneration. The processes that lead to tauopathy and subsequent dementia after TBI remain unclear. Here, we built upon the finding that seizures after TBI may be a mechanism leading to tauopathy, by dissecting the functions of the metabotropic glutamate receptor 5 - cellular prion protein (mGluR5-PrPC) pathway. We delivered TBI to larval in a blast paradigm, and quantified aggregation of Tau via a genetically-encoded Tau-GFP fusion reporter. Zebrafish larvae lacking prp2 (homolog of mammalian cellular Prion Protein, PrPC) displayed a 168% increase in post-traumatic seizures activity after TBI. An mGluR5 agonist (CHPG) reduced post-traumatic seizures, whereas an mGluR5 antagonist (MPEP) increased post-traumatic seizures. Moreover, agonizing mGluR5 reduced tau aggregation and antagonizing mGluR5 increased tau burden. Larvae seizing from convulsants, rather than TBI, were treated with CHPG/MPEP and provided a similar pattern of outcomes, suggesting seizures may be a factor needed for mGluR5 activity to influence tau aggregation. The PrPC-mGluR5 pathway is proposed as one candidate pathomechanism linking TBI to subsequent seizures and tauopathy, and thus it warrants investigation as a target for prophylactic interventions.

neuroscience↗