α2-containing GABAA receptors expressed in hippocampal region CA3 control fast network oscillations.

GABA(A) receptors are critically involved in hippocampal oscillations. GABA(A) receptor α1 and α2 subunits are differentially expressed throughout the hippocampal circuitry and thereby may have distinct contributions to oscillations. It is unknown which GABA(A) receptor α subunit controls hippocampal oscillations and where these receptors are expressed. To address these questions we used transgenic mice expressing GABA(A) receptor α1 and/or α2 subunits with point mutations (H101R) that render these receptors insensitive to allosteric modulation at the benzodiazepine binding site, and tested how increased or decreased function of α subunits affects hippocampal oscillations. Positive allosteric modulation by zolpidem prolonged decay kinetics of hippocampal GABAergic synaptic transmission and reduced the frequency of cholinergically induced oscillations. Allosteric modulation of GABAergic receptors in CA3 altered oscillation frequency in CA1, while modulation of GABA receptors in CA1 did not affect oscillations. In mice having a point mutation (H101R) at the GABA(A) receptor α2 subunit, zolpidem effects on cholinergically induced oscillations were strongly reduced compared to wild-type animals, while zolpidem modulation was still present in mice with the H101R mutation at the α1 subunit. Furthermore, genetic knockout of α2 subunits strongly reduced oscillations, whereas knockout of α1 subunits had no effect. Allosteric modulation of GABAergic receptors was strongly reduced in unitary connections between fast spiking interneurons and pyramidal neurons in CA3 of α2H101R mice, but not of α1H101R mice, suggesting that fast spiking interneuron to pyramidal neuron synapses in CA3 contain α2 subunits. These findings suggest that α2-containing GABA(A) receptors expressed in the CA3 region provide the inhibition that controls hippocampal rhythm during cholinergically induced oscillations.

Megalencephalic leucoencephalopathy with cysts: defect in chloride currents and cell volume regulation.

Megalencephalic leucoencephalopathy with subcortical cysts is a genetic brain disorder with onset in early childhood. Affected infants develop macrocephaly within the first year of life, after several years followed by slowly progressive, incapacitating cerebellar ataxia and spasticity. From early on, magnetic resonance imaging shows diffuse signal abnormality and swelling of the cerebral white matter, with evidence of highly increased white matter water content. In most patients, the disease is caused by mutations in the gene MLC1, which encodes a plasma membrane protein almost exclusively expressed in brain and at lower levels in leucocytes. Within the brain, MLC1 is mainly located in astrocyte-astrocyte junctions adjacent to the blood-brain and cereborspinal fluid-brain barriers. Thus far, the function of MLC1 has remained unknown. We tested the hypothesis that MLC1 mutations cause a defect in ion currents involved in water and ion homeostasis, resulting in cerebral white matter oedema. Using whole-cell patch clamp studies we demonstrated an association between MLC1 expression and anion channel activity in different cell types, most importantly astrocytes. The currents were absent in chloride-free medium and in cells with disease-causing MLC1 mutations. MLC1-dependent currents were greatly enhanced by hypotonic pretreatment causing cell swelling, while ion channel blockers, including Tamoxifen, abolished the currents. Down regulation of endogenous MLC1 expression in astrocytes by small interfering RNA greatly reduced the activity of this channel, which was rescued by overexpression of normal MLC1. The current-voltage relationship and the pharmacological profiles of the currents indicated that the channel activated by MLC1 expression is a volume-regulated anion channel. Such channels are involved in regulatory volume decrease. We showed that regulatory volume decrease was hampered in lymphoblasts from patients with megalencephalic leucoencephalopathy. A similar trend was observed in astrocytes with decreased MLC1 expression; this effect was rescued by overexpression of normal MLC1. In the present study, we show that absence or mutations of the MLC1 protein negatively impact both volume-regulated anion channel activity and regulatory volume decrease, indicating that megalencephalic leucoencephalopathy is caused by a disturbance of cell volume regulation mediated by chloride transport.

Altered temporal correlations in parietal alpha and prefrontal theta oscillations in early-stage Alzheimer disease.

Encoding and retention of information in memory are associated with a sustained increase in the amplitude of neuronal oscillations for up to several seconds. We reasoned that coordination of oscillatory activity over time might be important for memory and, therefore, that the amplitude modulation of oscillations may be abnormal in Alzheimer disease (AD). To test this hypothesis, we measured magnetoencephalography (MEG) during eyes-closed rest in 19 patients diagnosed with early-stage AD and 16 age-matched control subjects and characterized the autocorrelation structure of ongoing oscillations using detrended fluctuation analysis and an analysis of the life- and waiting-time statistics of oscillation bursts. We found that Alzheimer's patients had a strongly reduced incidence of alpha-band oscillation bursts with long life- or waiting-times (< 1 s) over temporo-parietal regions and markedly weaker autocorrelations on long time scales (1-25 seconds). Interestingly, the life- and waiting-times of theta oscillations over medial prefrontal regions were greatly increased. Whereas both temporo-parietal alpha and medial prefrontal theta oscillations are associated with retrieval and retention of information, metabolic and structural deficits in early-stage AD are observed primarily in temporo-parietal areas, suggesting that the enhanced oscillations in medial prefrontal cortex reflect a compensatory mechanism. Together, our results suggest that amplitude modulation of neuronal oscillations is important for cognition and that indices of amplitude dynamics of oscillations may prove useful as neuroimaging biomarkers of early-stage AD.

Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex.

Nicotine enhances attention and working memory by activating nicotinic acetylcholine receptors (nAChRs). The prefrontal cortex (PFC) is critical for these cognitive functions and is also rich in nAChR expression. Specific cellular and synaptic mechanisms underlying nicotine's effects on cognition remain elusive. Here we show that nicotine exposure increases the threshold for synaptic spike-timing-dependent potentiation (STDP) in layer V pyramidal neurons of the mouse PFC. During coincident presynaptic and postsynaptic activity, nicotine reduces dendritic calcium signals associated with action potential propagation by enhancing GABAergic transmission. This results from a series of presynaptic actions involving different PFC interneurons and multiple nAChR subtypes. Pharmacological block of nAChRs or GABA(A) receptors prevented nicotine's actions and restored STDP, as did increasing dendritic calcium signals with stronger postsynaptic activity. Thus, by activating nAChRs distributed throughout the PFC neuronal network, nicotine affects PFC information processing and storage by increasing the amount of postsynaptic activity necessary to induce STDP.

Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity.

Diacylglycerol (DAG) is a prominent endogenous modulator of synaptic transmission. Recent studies proposed two apparently incompatible pathways, via protein kinase C (PKC) and via Munc13. Here we show how these two pathways converge. First, we confirm that DAG analogs indeed continue to potentiate transmission after PKC inhibition (the Munc13 pathway), but only in neurons that previously experienced DAG analogs, before PKC inhibition started. Second, we identify an essential PKC pathway by expressing a PKC-insensitive Munc18-1 mutant in munc18-1 null mutant neurons. This mutant supported basic transmission, but not DAG-induced potentiation and vesicle redistribution. Moreover, synaptic depression was increased, but not Ca2+-independent release evoked by hypertonic solutions. These data show that activation of both PKC-dependent and -independent pathways (via Munc13) are required for DAG-induced potentiation. Munc18-1 is an essential downstream target in the PKC pathway. This pathway is of general importance for presynaptic plasticity.

Diacylglycerol lipase is not involved in depolarization-induced suppression of inhibition at unitary inhibitory connections in mouse hippocampus.

Endocannabinoids control hippocampal inhibitory synaptic transmission through activation of presynaptic CB(1) receptors. During depolarization-induced suppression of inhibition (DSI), endocannabinoids are synthesized upon postsynaptic depolarization. The endocannabinoid 2-arachidonoylglycerol (2-AG) may mediate hippocampal DSI. Currently, the best studied pathway for biosynthesis of 2-AG involves the enzyme diacylglycerol lipase (DAGL). However, whether DAGL is necessary for hippocampal DSI is controversial and was not systematically addressed. Here, we investigate DSI at unitary connections between CB(1) receptor-containing interneurons and pyramidal neurons in CA1. We found that the novel DAGL inhibitor OMDM-188, as well as the established inhibitor RHC-80267, did not affect DSI. As reported previously, effects of the DAGL inhibitor tetrahydrolipstatin depended on the application method: postsynaptic intracellular application left DSI intact, while incubation blocked DSI. We show that all DAGL inhibitors tested block slow self-inhibition in neocortical interneurons, which involves DAGL. We conclude that DAGL is not involved in DSI at unitary connections in hippocampus.

Fast network oscillations in vitro exhibit a slow decay of temporal auto-correlations.

Ongoing neuronal oscillations in vivo exhibit non-random amplitude fluctuations as reflected in a slow decay of temporal auto-correlations that persist for tens of seconds. Interestingly, the decay of auto-correlations is altered in several brain-related disorders, including epilepsy, depression and Alzheimer's disease, suggesting that the temporal structure of oscillations depends on intact neuronal networks in the brain. Whether structured amplitude modulation occurs only in the intact brain or whether isolated neuronal networks can also give rise to amplitude modulation with a slow decay is not known. Here, we examined the temporal structure of cholinergic fast network oscillations in acute hippocampal slices. For the first time, we show that a slow decay of temporal correlations can emerge from synchronized activity in isolated hippocampal networks from mice, and is maximal at intermediate concentrations of the cholinergic agonist carbachol. Using zolpidem, a positive allosteric modulator of GABA(A) receptor function, we found that increased inhibition leads to longer oscillation bursts and more persistent temporal correlations. In addition, we asked if these findings were unique for mouse hippocampus, and we therefore analysed cholinergic fast network oscillations in rat prefrontal cortex slices. We observed significant temporal correlations, which were similar in strength to those found in mouse hippocampus and human cortex. Taken together, our data indicate that fast network oscillations with temporal correlations can be induced in isolated networks in vitro in different species and brain areas, and therefore may serve as model systems to investigate how altered temporal correlations in disease may be rescued with pharmacology.

Flexible spike timing of layer 5 neurons during dynamic beta oscillation shifts in rat prefrontal cortex.

Human brain oscillations occur in different frequency bands that have been linked to different behaviours and cognitive processes. Even within specific frequency bands such as the beta- (14-30 Hz) or gamma-band (30-100 Hz), oscillations fluctuate in frequency and amplitude. Such frequency fluctuations most probably reflect changing states of neuronal network activity, as brain oscillations arise from the correlated synchronized activity of large numbers of neurons. However, the neuronal mechanisms governing the dynamic nature of amplitude and frequency fluctuations within frequency bands remain elusive. Here we show that in acute slices of rat prefrontal cortex (PFC), carbachol-induced oscillations in the beta-band show frequency and amplitude fluctuations. Fast and slow non-harmonic frequencies are distributed differentially over superficial and deep cortical layers, with fast frequencies being present in layer 3, while layer 6 only showed slow oscillation frequencies. Layer 5 pyramidal cells and interneurons experience both fast and slow frequencies and they time their spiking with respect to the dominant frequency. Frequency and phase information is encoded and relayed in the layer 5 network through timed excitatory and inhibitory synaptic transmission. Our data indicate that frequency fluctuations in the beta-band reflect synchronized activity in different cortical subnetworks, that both influence spike timing of output layer 5 neurons. Thus, amplitude and frequency fluctuations within frequency bands may reflect activity in distinct cortical neuronal subnetworks that may process information in a parallel fashion.

Inbred mouse strains differ in multiple hippocampal activity traits.

A major challenge in neuroscience is to identify genes that influence specific behaviors and to understand the intermediary neuronal mechanisms. One approach is to identify so-called endophenotypes at different levels of neuronal organization from synapse to brain activity. An endophenotype is a quantitative trait that is closer to the gene action than behavior, and potentially a marker of neuronal mechanisms underlying behavior. Hippocampal activity and, in particular, hippocampal oscillations have been suggested to underlie various cognitive and motor functions. To identify quantitative traits that are potentially useful for identifying genes influencing hippocampal activity, we measured gamma oscillations and spontaneous activity in acute hippocampal slices from eight inbred mouse strains under three experimental conditions. We estimated the heritability of more than 200 quantitative traits derived from this activity. We observed significant differences between the different mouse strains, particularly in the amplitude of the activity and the correlation between activities in different hippocampal subregions. Interestingly, these traits had a low genetic correlation between the three experimental conditions, which suggests that different genetic components influence the activity in different conditions. Our findings show that several traits of hippocampal gamma oscillations and spontaneous activity are heritable and could thus be potentially useful in gene-finding strategies based on endophenotypes.

Genetic contributions to long-range temporal correlations in ongoing oscillations.

The amplitude fluctuations of ongoing oscillations in the electroencephalographic (EEG) signal of the human brain show autocorrelations that decay slowly and remain significant at time scales up to tens of seconds. We call these long-range temporal correlations (LRTC). Abnormal LRTC have been observed in several brain pathologies, but it has remained unknown whether genetic factors influence the temporal correlation structure of ongoing oscillations. We recorded the ongoing EEG during eyes-closed rest in 390 monozygotic and dizygotic twins and investigated the temporal structure of ongoing oscillations in the alpha- and beta-frequency bands using detrended fluctuation analysis (DFA). The strength of LRTC was more highly correlated in monozygotic than in dizygotic twins. Statistical analysis attributed up to approximately 60% of the variance in DFA to genetic factors, indicating a high heritability for the temporal structure of amplitude fluctuations in EEG oscillations. Importantly, the DFA and EEG power were uncorrelated. LRTC in ongoing oscillations are robust, heritable, and independent of power, suggesting that LRTC and oscillation power are governed by distinct biophysical mechanisms and serve different functions in the brain. We propose that the DFA method is an important complement to classical spectral analysis in fundamental and clinical research on ongoing oscillations.

Nicotinic modulation of neuronal networks: from receptors to cognition.

RATIONALE: Nicotine affects many aspects of human cognition, including attention and memory. Activation of nicotinic acetylcholine receptors (nAChRs) in neuronal networks modulates activity and information processing during cognitive tasks, which can be observed in electroencephalograms (EEGs) and functional magnetic resonance imaging studies. OBJECTIVES: In this review, we will address aspects of nAChR functioning as well as synaptic and cellular modulation important for nicotinic impact on neuronal networks that ultimately underlie its effects on cognition. Although we will focus on general mechanisms, an emphasis will be put on attention behavior and nicotinic modulation of prefrontal cortex. In addition, we will discuss how nicotinic effects at the neuronal level could be related to its effects on the cognitive level through the study of electrical oscillations as observed in EEGs and brain slices. RESULTS/CONCLUSIONS: Very little is known about mechanisms of how nAChR activation leads to a modification of electrical oscillation frequencies in EEGs. The results of studies using pharmacological interventions and transgenic animals implicate some nAChR types in aspects of cognition, but neuronal mechanisms are only poorly understood. We are only beginning to understand how nAChR distribution in neuronal networks impacts network functioning. Unveiling receptor and neuronal mechanisms important for nicotinic modulation of cognition will be instrumental for treatments of human disorders in which cholinergic signaling have been implicated, such as schizophrenia, attention deficit/hyperactivity disorder, and addiction.

Oxytocin regulates neurosteroid modulation of GABA(A) receptors in supraoptic nucleus around parturition.

In this study, we investigate how neurosteroid sensitivity of GABA(A) receptors (GABA(A)Rs) is regulated. We examined this issue in neurons of the supraoptic nucleus (SON) of the rat and found that, during parturition, the GABA(A)Rs become insensitive to the neurosteroid allopregnanolone attributable to a shift in the balance between the activities of endogenous Ser/Thr phosphatase and PKC. In particular, a constitutive endogenous tone of oxytocin within the SON after parturition suppressed neurosteroid sensitivity of GABA(A)Rs via activation of PKC. Vice versa before parturition, during late pregnancy, application of exogenous oxytocin brings the GABA(A)Rs from a neurosteroid-sensitive mode toward a condition in which the receptors are not sensitive. This indicates that there may be an inverse causal relationship between the extent to which the GABA(A)R or one of its interacting proteins is phosphorylated and the neurosteroid sensitivity of the GABA(A)R. Neurosteroid sensitivity was not affected by changes in subunit composition of GABA(A)Rs known to occur concurrently in these cells.

Somatodendritic secretion in oxytocin neurons is upregulated during the female reproductive cycle.

During the female reproductive cycle, hypothalamic oxytocin (OT) neurons undergo sharp changes in excitability. In lactating mammals, bursts of electrical activity of OT neurons result in the release of large amounts of OT in the bloodstream, which causes milk ejection. One hypothesis is that OT neurons regulate their own firing activity and that of nearby OT neurons by somatodendritic release of OT. In this study, we show that OT neuron activity strongly reduces inhibitory synaptic transmission to these neurons. This effect is blocked by antagonists of both adenosine and OT receptors and is mimicked by OT application. Inhibition of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex formation by tetanus toxin completely blocked the stimulation-induced reduction in inhibitory input, as did the calcium chelator BAPTA. During lactation, the readily releasable pool of secretory vesicles in OT cell bodies was doubled, and calcium currents were upregulated. This resulted in an increased inhibition of GABAergic synaptic transmission by somatodendritic release during lactation compared with the adult virgin stage. These results demonstrate that somatodendritic release is augmented during lactation, which is a novel form of plasticity to change the strength of synaptic transmission.

Role of synaptic inhibition in spatiotemporal patterning of cortical activity.

Developmental upregulation of the GABAA receptor alpha1 subunit causes a faster decay of GABAergic inhibitory postsynaptic currents (IPSCs) in the visual cortex around the time of eye opening. In alpha1 deficient mice, a juvenile type of GABAA receptors is retained during maturation. As a result the decay time of the IPSCs is longer in alpha1-/- mice than in WT mice during the whole life span of the mice. Hence they form a valuable mouse model for studies on cellular aspects of neuronal network functioning. Using voltage sensitive dye imaging methods, we monitored the spatiotemporal excitation patterning in visual cortex slices upon local stimulation of the network. We found that in the alpha1-/- mice, the ability of the network to fire synchronously at gamma-frequencies (20-50 Hz) is diminished. This finding indicates that early onset of GABA synapse maturation is required for the normal neuronal network function in the maturating visual cortex.

Short-term modulation of GABAA receptor function in the adult female rat.

Oxytocin neurons in the supraoptic nucleus (SON) exhibit marked neuronal plasticity during each reproductive cycle. We have previously shown that this neuronal plasticity includes GABAA receptor subunit switching around the time of parturition. Here we focus on addition plasticity in short-term regulatory mechanisms of postsynaptic receptor function before and after parturition, i.e. alterations in metabotropic and allosteric modulation of GABAA receptor activity. Both short- and long-term regulation of the GABAA receptor function affects the electrical behaviour of the oxytocin neurons (Brussaard and Herbison, 2000); however, their causal linkage until recently remained unclear. Non-genomic gonadal steroid feedback to oxytocin neurons is mediated via the neurosteroid allopregnanolone (3 alpha-OH-DHP) that is an allosteric modulator of postsynaptic GABAA receptors. We recently found evidence to support the idea that (1) neurosteroids not only potentiate GABAA receptor function but also prevent its suppression by PKC (Brussaard et al., 2000), and (2) that neurosteroid sensitivity of GABAA receptor is not regulated by subunit switching, but instead, is dependent on the balance between endogenous phosphatase and PKC activity (Koksma et al., 2002). Thus, before pregnancy, the GABAA receptors are sensitive to 3 alpha-OH-DHP, due to a constitutively high level of phosphatase activity. At parturition, endogenous release of oxytocin within the SON shifts the intracellular balance towards a higher level of phosphorylation, leading to 3 alpha-OH-DHP insensitivity of the GABAA receptors. Here we discuss the putative mechanisms underlying these changes in receptor physiology, their causal relations and the functional significance for the hormonal output.

Conditional regulation of neurosteroid sensitivity of GABAA receptors.

Nongenomic gonadal steroid feedback to oxytocin containing neurons in the supraoptic nucleus of the hypothalamus is mediated via the neurosteroid allopregnanolone (3alpha-OH-DHP) that acts as an allosteric modulator of the postsynaptic GABA(A) receptors. We found evidence to support the idea that neurosteroids not only potentiate GABA(A) receptor function but also prevent its suppression by PKC. In addition, we found that neurosteroid sensitivity of GABA(A) receptor itself is dependent on the balance between endogenous phosphatase and PKC activity and not, as previously suggested, on subunit composition changes of the GABA(A) receptor. These data imply that native GABA(A) receptors are only sensitive to 3alpha-OH-DHP if there is endogenous phosphatase activity. In contrast, when, due to endogenous release of oxytocin in the hypothalamus, the intracellular balance is shifted from high phosphatase activity toward a higher level of PKC-dependent phosphorylation, this leads to 3alpha-OH-DHP-insensitivity of the GABA(A) receptors. How the regulatory mechanisms of the GABA(A) receptor physiology for the hypothalamus may also account for alterations in GABA transmission observed in other brain areas is discussed.

Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction.

Nicotine reinforces smoking behaviour by activating nicotinic acetylcholine receptors in the midbrain dopaminergic reward centres. Upstream of the dopaminergic neurons nicotine induces long-term potentiation of the excitatory input to dopamine cells in the ventral tegmental area, and depresses inhibitory inputs. Both effects of nicotine were shown to last much longer than the nicotine exposure and together will activate the dopaminergic ventral tegmental area projection toward the nucleus accumbens. However, downstream of dopamine, effects of nicotine are also likely to occur. Cholinergic interneurons within the nucleus accumbens are important in the tonic control of the gamma-amino buteric acid (GABA) nucleus accumbens output neurons, which project back to the ventral tegmental area. The nicotinic acetylcholine receptors that mediate this control are likely to desensitise upon preexposure to the nicotine concentrations found in the blood of smokers. Thus, synaptic mechanisms both upstream and downstream of dopamine release are potentially important factors contributing to the etiology of nicotine addiction.

Novel candidate genes associated with hippocampal oscillations.

The hippocampus is critical for a wide range of emotional and cognitive behaviors. Here, we performed the first genome-wide search for genes influencing hippocampal oscillations. We measured local field potentials (LFPs) using 64-channel multi-electrode arrays in acute hippocampal slices of 29 BXD recombinant inbred mouse strains. Spontaneous activity and carbachol-induced fast network oscillations were analyzed with spectral and cross-correlation methods and the resulting traits were used for mapping quantitative trait loci (QTLs), i.e., regions on the genome that may influence hippocampal function. Using genome-wide hippocampal gene expression data, we narrowed the QTLs to eight candidate genes, including Plcb1, a phospholipase that is known to influence hippocampal oscillations. We also identified two genes coding for calcium channels, Cacna1b and Cacna1e, which mediate presynaptic transmitter release and have not been shown to regulate hippocampal network activity previously. Furthermore, we showed that the amplitude of the hippocampal oscillations is genetically correlated with hippocampal volume and several measures of novel environment exploration.

GABAergic synapse properties may explain genetic variation in hippocampal network oscillations in mice.

Cognitive ability and the properties of brain oscillation are highly heritable in humans. Genetic variation underlying oscillatory activity might give rise to differences in cognition and behavior. How genetic diversity translates into altered properties of oscillations and synchronization of neuronal activity is unknown. To address this issue, we investigated cellular and synaptic mechanisms of hippocampal fast network oscillations in eight genetically distinct inbred mouse strains. The frequency of carbachol-induced oscillations differed substantially between mouse strains. Since GABAergic inhibition sets oscillation frequency, we studied the properties of inhibitory synaptic inputs (IPSCs) received by CA3 and CA1 pyramidal cells of three mouse strains that showed the highest, lowest and intermediate frequencies of oscillations. In CA3 pyramidal cells, the frequency of rhythmic IPSC input showed the same strain differences as the frequency of field oscillations. Furthermore, IPSC decay times in both CA1 and CA3 pyramidal cells were faster in mouse strains with higher oscillation frequencies than in mouse strains with lower oscillation frequency, suggesting that differences in GABA(A)-receptor subunit composition exist between these strains. Indeed, gene expression of GABA(A)-receptor ß2 (Gabrb2) and ß3 (Gabrb2) subunits was higher in mouse strains with faster decay kinetics compared with mouse strains with slower decay kinetics. Hippocampal pyramidal neurons in mouse strains with higher oscillation frequencies and faster decay kinetics fired action potential at higher frequencies. These data indicate that differences in genetic background may result in different GABA(A)-receptor subunit expression, which affects the rhythm of pyramidal neuron firing and fast network activity through GABA synapse kinetics.

GABAergic inhibition shapes frequency adaptation of cortical activity in a frequency-dependent manner.

Primary sensory cortical areas continuously receive thalamic inputs that arrive at different frequencies depending on the amount of sensory activity. The cortical response to repeated sensory stimuli rapidly adapts and different frequencies recruit cortical neuronal networks to different extents. GABAergic inhibition limits the spread of excitation within cortical neuronal networks. However, it is unknown how frequency adaptation of cortical network activity at different frequencies is shaped by GABAergic inhibition. Here, we find that in acute slices of visual cortex area V1 GABAergic inhibition affects frequency adaptation depending on the frequency of activity. Using voltage-sensitive dye imaging, we found that while increasing inhibitory postsynaptic currents (IPSCs) with flunitrazepam dampened the spread of cortical excitation, short-term adaptations to different stimulation frequencies were differentially affected. At high frequencies (40 Hz), facilitation of cortical excitation was no longer transient, but facilitation was sustained. At low frequencies (10 Hz) flunitrazepam decreased a depression of the excitation. In contrast, in mice lacking the GABA(A) receptor alpha1 subunit facilitation was reduced and depression enhanced. These findings suggest that GABAergic inhibition affects cortical excitation at different frequencies differentially, favoring facilitation at higher frequencies of excitation.