The neural network is the substrate of brain function. The functional dynamics of neural networks modify the synaptic physiology, leading to the reorganization of these circuits [1]. These modifications modulate the firing of local units that determine the network’s functional state [2]. In the network’s functional state, neurons respond to both convergent and divergent inputs (from the network itself, recurrent local networks, or even distal networks), which can be excitatory or inhibitory. These dynamics effectively influence the output signals by modulating selective connections, leading to constant changes in the network pathways [3]. Thus, the balance between excitation and inhibition (E/I) is a fundamental parameter that influences the network’s output signal [4]. An imbalance in this parameter impacts the progression of various diseases ^[5][6][5,6].

Networks have a stable state in which they are not entirely inactive. In this state, the neuronal activity (including synaptic strength, intrinsic properties, and E/I balance) produces a broad spectrum of networks with various properties (size, dynamics, and linkage frameworks [7]). In an operational network, the temporal evolution between E/I is proportional among individual neurons and across the global network. This feature allows rapid transitions between states that translate into functional output signals [3]. Therefore, a process able to modulate the network state by controlling the temporal dynamics between E/I is functionally essential. This process is known as disinhibition.

Another essential signal modulation mechanism is gain control, which involves regulating the amplitude caused by the E/I balance ^[8][13]. In this framework, inhibition in the perisomatic region controls the gain of projection neuron responses, which modulates the arrangement of synaptic inputs ^[9][8]. In the network, gain control induces normalization of the average neuron firing rate according to the inputs ^[9][10][11][8,14,15]; therefore, inhibition adjusts the gain. Consequently, a regenerative depolarization that begins in the dendrites is the process by which distal excitatory inputs lead to neural activation; this process has been described in relation to disinhibition ^[12][16]. Neural network oscillations are involved in multiple physiological processes and are accepted as tools for communication among brain regions. Thus, oscillations lead to the organization and coordination of information due to the precise interactions among the activities of different neurons over time. The emergence of oscillations and their frequency ranges depend on both the intrinsic neuronal properties and the network properties ^[2][13][2,17]. Gamma-aminobutyric acid (GABA) is a canonical inhibitory neurotransmitter. GABA performs its function through three types of receptors: GABA_A, GABA_B, and GABA_C. The versatility of GABA is demonstrated not only in the diversity of receptors but also in how it establishes inhibition, with phasic and tonic forms. In the phasic form, the postsynaptic GABA_A receptor is activated by an increase in GABA in the synaptic cleft after release. In the tonic form, GABA overflows from the synaptic cleft and activates extrasynaptic GABA A receptors (located in the presynaptic terminal and synapses with adjacent neurons), allowing temporally and spatially slow transmission. The extrasynaptic receptors show a high affinity to GABA and mainly constitute the δ subunits assembled at α4 or α6 ^{[14][15][16][17]}[18,19,20,21].

2. Involvement of GABA B Receptors

GABA_B Rs are ubiquitous metabotropic receptors in the brain. These receptors couple with the Gi protein. Consequently, the G_αi/G_αo subunits inhibit adenylyl cyclase (AC), which reduces cAMP levels and thus decreases protein kinase A (PKA) activity ^[17][21]. The G_βγ subunits inhibit the Ca²⁺ channels and activate the GIRK and TREK-type K⁺ channels ^[18][23]. The affinity of the G_βγ subunit to GIRKs increases due to the Na⁺ that enters during the action potential; this increase in affinity leads to the opening of the channel ^[19][24]. GABA_B Rs are expressed at both inhibitory and excitatory synapses. They require two different subunits for their function: GABA_B1 and GABA_B2. GABA binds to the GABA_B1 subunit and the GABA_B2 subunit causes signaling ^[20][25]. Due to gene splicing, GABA_B1 has two isoforms, GABA_B1a and GABA_B1b, which have different N-N-terminal regions. This region determines that the GABA B1a isoform is expressed at the presynaptic terminal in excitatory synapses, thus modulating glutamate release ^[20][21][22][25,26,27].

2.1. Presynaptic Modulation

The critical presynaptic function of GABA_B Rs is inhibiting the release of neurotransmitters by restricting the entry of Ca²⁺ into the terminal, followed by the inhibition of VGCC by the G_βγ subunit. However, this is not the only mechanism of GABA_B Rs. GABA_B Rs also modulate the release mechanism at various levels. For example, they modulate the SNAP-25 protein by decreasing cAMP levels, which reduces vesicular priming. During this process, the G_βγ subunit modulates neurotransmitter release through direct interaction with the SNAP-25 protein, and this interaction is modulated by synaptotagmin-1 ^[23][29]. GABA_B Rs exert gain modulation at the network level through their presynaptic control. In olfactory inputs, they control differential presynaptic gain ^[24][32]. In the presynaptic neurons of the inferior colliculus, GABA_B Rs control the excitability gain, and blockading them increases adaptation to the stimulus ^[25][33]. 

2.2. Postsynaptic Modulation

The predominant effect at the postsynaptic level is the inhibition mediated by the activation of the GIRK channels by the G_βγ subunit ^[26][36]. Once active, the G_βγ subunit forms a complex with the RGS protein, which binds to the GIRKs and accelerates their kinetics ^[27][37]. At the same time, the RGS protein increases the GTPase activity of the Gα subunit, causing rapid desensitization of the K⁺ current ^[28][38], which reduces neuronal excitability and inhibits action potential backpropagation.

2.3. Modulation of Network Dynamics

GABA_B Rs modulate the dynamics in the network by decreasing the output current. Once activated, GABA_B Rs inhibit the N-type calcium and BK-type potassium channels. Consequently, the neurons increase their degree of depolarization, incrementing their excitation level ^[18][23]. It has been suggested that inhibiting the N-type channels leads to operational advantages by expanding the transmission dynamics without influencing neurotransmitter release ^[18][23]. In the lateral geniculate nucleus, the activation of GABA_B Rs leads to strong hyperpolarization, followed by rebound firing as mediated by the T-type Ca²⁺ channels, which improves the signal detectability while altering sensory discrimination ^[29][42]. GABA_B R activation in the network is related to burst firing and constant rhythmic activity. In this way, GABA_B Rs may temporally modulate slow network activity, the strength of fast activity, and the relative firing during network oscillations ^[30][43].

3. GABA Levels

Recent evidence suggests that the synaptic levels of GABA are essential to synaptic transmission and network physiology. Quantitative reports suggest that the synaptic GABA levels are in the mM range, while the extrasynaptic levels are in the μM range. However, in the nuclei of specific neurons, these levels are higher at rest and during physiological processes ^[26][36].

Accepted functional roles of the GABA levels in both synaptic transmission and the network dynamics include the generation of tonic current and the activation of extrasynaptic GABA_A and GABA_B Rs (including subtypes of both receptors sensitive to low GABA concentrations ^[31][46]). 

It is evident that GABA (by controlling the generation of membrane potential with different forms in various regions) modulates the temporal integration of synaptic inputs and, consequently, the activity patterns of the neuronal populations that make up the circuits, with the tonic current playing a fundamental role. Thus, the stimulating current is modulated by different processes, including the sustained activation of individual cells, the coordination of presynaptic events of different interneurons, an increase in the current density at the release site, and the reuptake mechanisms, which depend on the transporters. GABA transporters (GATs) are widely expressed in multiple nuclei, compartments, and neuronal glia, with a higher expression in axons than dendrites ^[32][47]. The function of GATs depends on several factors. First, the amplitude of the receptor activation is transiently modulated by the GABA concentration. Second, GATs control the receptor kinetics during the recruitment of neighboring synapses. Third, GATs are involved in spatial transmission; they convert spatially confined inhibitory signals into waves without spatial restrictions, which can activate type A or B receptors at both the presynaptic and postsynaptic terminals ^[31][33][46,48]. The contribution of GABA Rs to tonic current has been described. Studies on neurons in the locus ceruleus suggest that GABA_B Rs generate tonic currents through ERK1-dependent activation ^[34][50]. In the basal amygdala, an increase in tonic inhibition related to presynaptic regulation was reported ^[35][51].

4. Disinhibition

Functionally, a microcircuit may have a “disinhibiting” motif, including serial connections between two inhibitory interneurons and a principal excitatory neuron ^[36][58]. These circuits are involved in the response to social fear. In this process, the increase in the activity of somatostatin (SST)-positive interneurons (INs) inhibits parvalbumin-positive (PV+) INs, which causes disinhibition of the principal cells of the dorsomedial prefrontal cortex ^[37][59]. An interesting disinhibitory process was described in the lateral entorhinal cortex. In it, optogenetic silencing of VIP INs (positive for vasoactive intestinal peptide) significantly decreased the incidence of the dendritic spikes driven by the lateral entorhinal cortex, suggesting a disinhibitory effect being exerted on the dendritic activity by the INs ^[38][61]. A disinhibitory process at the dendritic level was described in the hippocampus associated with the LTP process ^[39][62]. The VIP INs in the hippocampus regulate LTP through disinhibition by activating the VPAC1 receptors (G protein-coupled receptors of the VIP/PACAP family). This molecular mechanism affects the expression and phosphorylation of the K_v4.2 K⁺ channels in the dendrites of the hippocampal pyramidal cells ^[40][11]. During attentional selection, selective disinhibition improved the target firing rates with resemblance to multiplicative input gain, another commonly reported effect of attention on neural responses ^[41][63]. In the cerebellum, the activation of GABA_B Rs in the dentate gyrus (DG) improves the granule cell (GC) activity by reducing the synaptic inhibition imposed by hilar INs. This disinhibitory action facilitates the transfer of signals from the hippocampus. Tourette’s syndrome (TS) is a hyperkinetic disorder characterized by motor and phonetic tics ^[42][43][73,74]. However, its clinical presentation is commonly accompanied by various abnormal behaviors (motor, sensory, and complex behavioral), such as inappropriate non-obscene behaviors, impulsivity, obsessive-compulsive disorder, and attention deficit hyperactivity disorder ^[43][74] The central pathophysiological substrate is disinhibition ^[42][43][44][10,73,74]. This originates from alterations in the GABAergic signaling and a loss of E/I balance in the cortex–basal ganglia–thalamus–cortex circuit associated with the modulation of motor output, motor learning, and action selection.

5. Oscillation

Various compelling studies have described the modulatory participation of GABA_B Rs in slow cortical oscillations. During slow wave oscillations (SWOs), GABA_B R blockade modifies three important aspects of the SWO cycle. First, GABA_B R blockade increases the number of “up” states; second, GABA_B R blockade affects the subsequent duration of the “down” state; and third, GABA_B R activation desynchronizes the SWOs ^[45][79]. The participation of GABA_B Rs according to their synaptic location has also been described. At the presynaptic level, GABA_B Rs contribute to spontaneous transitions from the down state, while postsynaptic receptors are essential for the afferent termination of the up state. Thus, GABA_B Rs containing the GABA subunit contribute to spontaneous termination of the up state, and GABA_B Rs containing the GABA_B1b subunit are essential for afferent evoked termination of the upstate ^[46][80]. Thalamic oscillations of 3 to 5 Hz are characteristic of absence epilepsy. In a rodent model, selectively blocking the GABA transporters ([GAT] to GAT-1 or GAT-3) was shown to prolong the oscillations; however, blocking both transporters inhibited the oscillations. In this same model, it was reported that extending the activity in a narrow range of GABA_B Rs promoted the opening of T-type channels and intensified the oscillations ^[47][82]. In addition, tonic inhibition and disinhibition have been suggested to regulate motor activity ^[48][83]. An analysis of the cortical oscillations after GAT-1 blockade demonstrated that high GABA levels influence the beta oscillations related to movement ^[49][84]. Recently, it was reported that high GABA levels and the participation of GABA_B Rs in the external globus pallidus disinhibit the RTn and thus desynchronize the beta oscillations in the motor cortex [65,66].