Figure - available from: Brain Structure and Function
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Schematic diagram illustrating the modulation of glutamate presynaptic releases and postsynaptic responses by GABABRs onto SG neurons in the dorsal horn. At the presynaptic (upper broken line rectangle), ambient GABA binds glutamatergic terminals (indicated by ①) and/or spillover GABA from GABAergic terminals (indicated by ②), subsequently modulates the glutamatergic synapse. Note ambient GABA comes from escapee of GABAergic synaptic release, GABA reuptake (not shown in this figure) and/or glial cells (indicated by blue arrows). At the postsynaptic (lower broken line rectangle), GABABRs, activated by baclofen, impair postsynaptic glutamate response (see “Results”), with an uncertain mechanism (indicated by a question mark)
Source publication
The substantia gelatinosa (SG, lamina II of spinal cord gray matter) is pivotal for modulating nociceptive information from the peripheral to the central nervous system. γ-Aminobutyric acid type B receptors (GABABRs), the metabotropic GABA receptor subtype, are widely expressed in pre- and postsynaptic structures of the SG. Activation of GABABRs by...
Citations
... 41 Particularly, GABA A in the dorsal horn is found in both presynaptic and postsynaptic neurons, mediating presynaptic inhibition and primary afferent depolarization, correspondingly. 42 Extra-synaptic α5-GABA A on the proprioceptive afferent neurons leads to tonic depolarization of the spinal cord via modulation of Na 2+ channels. 43 Furthermore, GABAergic neurons are excitatory at prenatal and postnatal periods; nevertheless, these neurons endure developmental changes from excitatory to inhibitory. ...
Background
Parkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non‐motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ‐aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non‐motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD.
Aim
Sleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD‐related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non‐motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non‐motor symptoms.
Conclusion
There is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation.
Activating primary afferent TRPV1-positive (TRPV1⁺) fibers in the spinal dorsal horn triggers exaggerated glutamate release and induces acute pain. However, whether the glutamate postsynaptic responses on dorsal horn neurons are regulated by excessive glutamate is unknown, largely due to intrinsic technical difficulties. In the present study, capsaicin, a specific TRPV1 agonist, was used to activate TRPV1⁺ fibers in the spinal dorsal horn. Combining three-dimensional (3-D) holographic photostimulation and whole-cell recordings on acute spinal cord slices from adult rodents, we found that postsynaptic glutamate responses were attenuated when activating TRPV1⁺ fibers with capsaicin. Electron microscopy and Western blot studies found that postsynaptic GluA1 (a subtype of ionotropic glutamate receptors) on the postsynaptic membrane was decreased by acute capsaicin treatment. Therefore, postsynaptic glutamate receptor occupancy and/or downmodulation may underlie this postsynaptic attenuation. Our data thus clarify a scenario in which postsynaptic glutamate responses are largely downregulated upon TRPV1⁺ activation, and this change may contribute to homeostasis in the dorsal horn circuit when “acute pain” occurs.
