Competition, Conflict and Change of Mind: A Role of GABAergic Inhibition in the Primary Motor Cortex

Deciding between different voluntary movements implies a continuous control of the competition between potential actions. Many theories postulate a leading role of prefrontal cortices in this executive function, but strong evidence exists that a motor region like the primary motor cortex (M1) is also involved, possibly via inhibitory mechanisms. This was already shown during the pre-movement decision period, but not after movement onset. For this pilot experiment we designed a new task compatible with the dynamics of post-onset control to study the silent period (SP) duration, a pause in electromyographic activity after single-pulse transcranial magnetic stimulation that reflects inhibitory mechanisms. A careful analysis of the SP during the ongoing movement indicates a gradual increase in inhibitory mechanisms with the level of competition, consistent with an increase in mutual inhibition between alternative movement options. However, we also observed a decreased SP duration for high-competition trials associated with change-of-mind inflections in their trajectories. Our results suggest a new post-onset adaptive process that consists in a transient reduction of GABAergic inhibition within M1 for highly conflicting situations. We propose that this reduced inhibition softens the competition between concurrent motor options, thereby favoring response vacillation, an adaptive strategy that proved successful at improving behavioral performance.

Krešimir Krnjević (1927–2021) and GABAergic inhibition: a lifetime dedication

After over seven decades of neuroscience research, it is now well established that γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. In this paper dedicated to Krešimir Krnjević (1927–2021), a pioneer and leader in neuroscience, we briefly highlight the fundamental contributions he made in identifying GABA as an inhibitory neurotransmitter in the brain and our personal interactions with him. Of note, between 1972 and 1978 Dr. Krnjević was a highly reputed Chief Editor of the Canadian Journal of Physiology and Pharmacology.

Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases

The neuro-physiological properties of individuals with genetic pre-disposition to neurological disorders are largely unknown. Here we aimed to explore these properties using cerebral organoids (COs) derived from fibroblasts of individuals with confirmed genetic mutations including PRNPE200K, trisomy 21 (T21), and LRRK2G2019S, which are associated with Creutzfeldt Jakob disease, Down Syndrome, and Parkinson’s disease. We utilized no known disease/healthy COs (HC) as normal function controls. At 3–4 and 6–10 months post-differentiation, COs with mutations showed no evidence of disease-related pathology. Electrophysiology assessment showed that all COs exhibited mature neuronal firing at 6–10 months old. At this age, we observed significant changes in the electrophysiology of the COs with disease-associated mutations (dCOs) as compared with the HC, including reduced neuronal network communication, slowing neuronal oscillations, and increased coupling of delta and theta phases to the amplitudes of gamma oscillations. Such changes were linked with the detection of hypersynchronous events like spike-and-wave discharges. These dysfunctions were associated with altered production and release of neurotransmitters, compromised activity of excitatory ionotropic receptors including receptors of kainate, AMPA, and NMDA, and changed levels and function of excitatory glutamatergic synapses and inhibitory GABAergic synapses. Neuronal properties that modulate GABAergic inhibition including the activity of Na–K-Cl cotransport 1 (NKCC1) in Cl− homeostasis and the levels of synaptic and extra-synaptic localization of GABA receptors (GABARs) were altered in the T21 COs only. The neurosteroid allopregnanolone, a positive modulator of GABARs, was downregulated in all the dCOs. Treatment with this neurosteroid significantly improved the neuronal communication in the dCOs, possibly through improving the GABAergic inhibition. Overall, without the manifestation of any disease-related pathology, the genetic mutations PRNPE200K, T21, and LRRK2G2019S significantly altered the neuronal network communication in dCOs by disrupting the excitatory-to-inhibitory balance.

GABA and IA Independently Regulate rNST Responses to Afferent Input

Taste responses in the rostral nucleus of the solitary tract (rNST) influence motivated ingestive behavior via ascending pathways, and consummatory reflex behavior via local, brainstem connections. Modifications to the afferent signal within the rNST include changes in gain (the overall rate of neuron activity) and changes in gustatory tuning (the degree to which individual neurons respond to divergent gustatory qualities). These alterations of the sensory signal derive from both synaptic interactions within the nucleus and the constitutive cellular membrane properties of rNST neurons. GABA neurons are well represented within the rNST, as is expression of KV4.3, a channel for a rapidly inactivating outward K+ current (IA). GABAergic synapses suppress rNST responses to afferent input and previous studies showed that this suppression is greater in cells expressing IA, suggesting a possible interaction. Here, we examine the potential interaction between GABAergic inhibition and IA channels in a series of patch clamp experiments. Optogenetic release of GABA suppressed rNST responses to afferent (electrical) stimulation and this effect was greater in cells with IA, confirming an earlier report. We further observed that the composite inhibitory postsynaptic potential was larger in IA positive cells, suggesting one mechanism for the greater afferent suppression. Blocking IA with the channel blocker AmmTX3, enhanced the response to afferent stimulation, suggesting a suppressive role for this channel in regulating afferent input at rest. However, pharmacologic blockade of IA did not suppress GABAergic inhibition, indicating that IA and GABA independently regulate excitatory afferent input.

Vitamins D and B12, Altered Synaptic Plasticity and Extracellular Matrix

Brain plasticity is regulated through dynamic interactions between perineuronal nets, matrix metalloproteases (MMPs) and the extracellular matrix (ECM). Several studies have identified a crucial role for vitamins D and B12 in brain development and a deficiency in these vitamins may contribute to the emergence of cognitive deficits, as well as the onset of both autism spectrum disorder and schizophrenia. However, the mechanisms underlying the interplay between ECM, MMPs, vitamins and these neuropsychiatric conditions are poorly understood. In this chapter, we seek to understand how the risk of neurodegeneration in vulnerable individuals and the aetiology of specific neuropsychiatric disorders are affected by vitamin D and B12 deficiency, in conjunction with low levels of the antioxidant glutathione, impaired GABAergic inhibition, and alterations in the permanent ECM.

GABAergic inhibition in the human visual cortex relates to eye dominance

Binocular vision is created by fusing the separate inputs arriving from the left and right eyes. ‘Eye dominance’ provides a measure of the perceptual dominance of one eye over the other. Theoretical models suggest that eye dominance is related to reciprocal inhibition between monocular units in the primary visual cortex, the first location where the binocular input is combined. As the specific inhibitory interactions in the binocular visual system critically depend on the presence of visual input, we sought to test the role of inhibition by measuring the inhibitory neurotransmitter GABA during monocular visual stimulation of the dominant and the non-dominant eye. GABA levels were measured in a single volume of interest in the early visual cortex, including V1 from both hemispheres, using a combined functional magnetic resonance imaging and magnetic resonance spectroscopy (combined fMRI-MRS) sequence on a 7-Tesla MRI scanner. Individuals with stronger eye dominance had a greater difference in GABAergic inhibition between the eyes. This relationship was present only when the visual system was actively processing sensory input and was not present at rest. We provide the first evidence that imbalances in GABA levels during ongoing sensory processing are related to eye dominance in the human visual cortex. Our finding supports the view that intracortical inhibition underlies normal eye dominance.