Pharmacological blocking of spinal GABAA receptors in monkeys reduces sensory transmission to the spinal cord, thalamus, and cortex

Amr A Mahrous; Lucy Liang; Josep-Maria Balaguer; Jonathan C Ho; Erinn M Grigsby; Vahagn Karapetyan; Arianna Damiani; Daryl P Fields; Jorge A Gonzalez-Martinez; Peter C Gerszten; David J Bennett; C J Heckman; Elvira Pirondini; Marco Capogrosso

doi:10.1016/j.celrep.2024.115100

Pharmacological blocking of spinal GABA_A receptors in monkeys reduces sensory transmission to the spinal cord, thalamus, and cortex

Cell Rep. 2024 Dec 18;44(1):115100. doi: 10.1016/j.celrep.2024.115100. Online ahead of print.

Affiliations

¹ Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
² Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA.
³ School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.
⁵ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada; Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB, Canada.
⁷ Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Department of Physical Therapy and Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Department of Physical Medicine and Rehabilitation, Shirley Ryan AbilityLab, Chicago, IL, USA.
⁸ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: elvirap@pitt.edu.
⁹ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: mcapo@pitt.edu.

PMID: 39700009
DOI: 10.1016/j.celrep.2024.115100

Abstract

A century of research established that GABA inhibits proprioceptive inputs presynaptically to sculpt spinal neural inputs into skilled motor output. Recent results in mice challenged this theory by showing that GABA can also facilitate action potential conduction in proprioceptive afferents. Here, we tackle this controversy in monkeys, the most human-relevant animal model, and show that GABA_A receptors (GABA_ARs) indeed facilitate sensory inputs to spinal motoneurons and interneurons and that this mechanism also influences sensory transmission to supraspinal centers. We performed causal manipulations of GABA_ARs with intrathecal pharmacology in anesthetized monkeys while recording electrical signals in the muscles, spinal cord, thalamus, and cortex. We show that blocking GABA_ARs suppresses spinal reflexes to hand muscles, sensory-evoked single-unit firing in the spinal cord, and sensory-evoked potentials in the thalamus and somatosensory cortex. Our results portray a sophisticated picture of presynaptic modulation of sensory inputs by GABA in the spinal cord.

Keywords: CP: Cell biology; CP: Neuroscience; GABA; GABA(A) receptors; hand; monkeys; presynaptic inhibition; primary afferent depolarization; sensory transmission; somatosensory cortex; spinal reflexes; thalamus.

Grants and funding

R01 NS131428/NS/NINDS NIH HHS/United States