Single genomic enhancers drive experience-dependent GABAergic plasticity to maintain sensory processing in the adult cortex.

Experience-dependent plasticity of synapses modulates information processing in neural circuits and is essential for cognitive functions. The genome, via non-coding enhancers, was proposed to control information processing and circuit plasticity by regulating experience-induced transcription of genes that modulate specific sets of synapses. To test this idea, we analyze here the cellular and circuit functions of the genomic mechanisms that control the experience-induced transcription of Igf1 (insulin-like growth factor 1) in vasoactive intestinal peptide (VIP) interneurons (INs) in the visual cortex of adult mice. We find that two sensory-induced enhancers selectively and cooperatively drive the activity-induced transcription of Igf1 to thereby promote GABAergic inputs onto VIP INs and to homeostatically control the ratio between excitation and inhibition (E/I ratio)-in turn, this restricts neural activity in VIP INs and principal excitatory neurons and maintains spatial frequency tuning. Thus, enhancer-mediated activity-induced transcription maintains sensory processing in the adult cortex via homeostatic modulation of E/I ratio.

An increase of inhibition drives the developmental decorrelation of neural activity.

Throughout development, the brain transits from early highly synchronous activity patterns to a mature state with sparse and decorrelated neural activity, yet the mechanisms underlying this process are poorly understood. The developmental transition has important functional consequences, as the latter state is thought to allow for more efficient storage, retrieval, and processing of information. Here, we show that, in the mouse medial prefrontal cortex (mPFC), neural activity during the first two postnatal weeks decorrelates following specific spatial patterns. This process is accompanied by a concomitant tilting of excitation-inhibition (E-I) ratio toward inhibition. Using optogenetic manipulations and neural network modeling, we show that the two phenomena are mechanistically linked, and that a relative increase of inhibition drives the decorrelation of neural activity. Accordingly, in mice mimicking the etiology of neurodevelopmental disorders, subtle alterations in E-I ratio are associated with specific impairments in the correlational structure of spike trains. Finally, capitalizing on EEG data from newborn babies, we show that an analogous developmental transition takes place also in the human brain. Thus, changes in E-I ratio control the (de)correlation of neural activity and, by these means, its developmental imbalance might contribute to the pathogenesis of neurodevelopmental disorders.

Bicuculline restores frequency-dependent hippocampal I/E ratio and circuit function in PGC-1ɑ null mice.

Altered inhibition/excitation (I/E) balance contributes to various brain disorders. Dysfunctional GABAergic interneurons enhance or reduce inhibition, resulting in I/E imbalances. Differences in short-term plasticity between excitation and inhibition cause frequency-dependence of the I/E ratio, which can be altered by GABAergic dysfunction. However, it is unknown whether I/E imbalances can be rescued pharmacologically using a single dose when the imbalance magnitude is frequency-dependent. Loss of PGC-1α (peroxisome proliferator activated receptor γ coactivator 1α) causes transcriptional dysregulation in hippocampal GABAergic interneurons. PGC-1α-/- slices have enhanced baseline inhibition onto CA1 pyramidal cells, causing increased I/E ratio and impaired circuit function. High frequency stimulation reduces the I/E ratio and recovers circuit function in PGC-1α-/- slices. Here we tested if using a low dose of bicuculline that can restore baseline I/E ratio can also rescue the frequency-dependent I/E imbalances in these mice. Remarkably, bicuculline did not reduce the I/E ratio below that of wild type during high frequency stimulation. Interestingly, bicuculline enhanced the paired-pulse ratio (PPR) of disynaptic inhibition without changing the monosynaptic inhibition PPR, suggesting that bicuculline modifies interneuron recruitment and not GABA release. Bicuculline improved CA1 output in PGC-1α-/- slices, enhancing EPSP-spike coupling to wild type levels at high and low frequencies. Our results show that it is possible to rescue frequency-dependent I/E imbalances in an animal model of transcriptional dysregulation with a single treatment.

The impact of Transcranial Magnetic Stimulation (TMS) on seizure course in people with and without epilepsy.

Objective: To elucidate the effects of single and paired-pulse TMS on seizure activity at electrographic and clinical levels in people with and without epilepsy. Methods: A cohort of 35 people with epilepsy, two people with alternating hemiplegia of childhood (AHC) with no epilepsy, and 16 healthy individuals underwent single or paired-pulse TMS combined with EEG. Clinical records and subject interviews were used to examine seizure frequency four weeks before and after TMS. Results: There were no significant differences in seizure frequency in any subject after TMS exposure. There was no occurrence of seizures in healthy individuals, and no worsening of hemiplegic attacks in people with AHC. Conclusions: No significant changes in seizure activity were found before or after TMS. Significance: This study adds evidence on the safety of TMS in people with and without epilepsy with follow-up of four weeks after TMS.

Dynamic interplay between thalamic activity and Cajal-Retzius cells regulates the wiring of cortical layer 1.

Cortical wiring relies on guidepost cells and activity-dependent processes that are thought to act sequentially. Here, we show that the construction of layer 1 (L1), a main site of top-down integration, is regulated by crosstalk between transient Cajal-Retzius cells (CRc) and spontaneous activity of the thalamus, a main driver of bottom-up information. While activity was known to regulate CRc migration and elimination, we found that prenatal spontaneous thalamic activity and NMDA receptors selectively control CRc early density, without affecting their demise. CRc density, in turn, regulates the distribution of upper layer interneurons and excitatory synapses, thereby drastically impairing the apical dendrite activity of output pyramidal neurons. In contrast, postnatal sensory-evoked activity had a limited impact on L1 and selectively perturbed basal dendrites synaptogenesis. Collectively, our study highlights a remarkable interplay between thalamic activity and CRc in L1 functional wiring, with major implications for our understanding of cortical development.

Presynaptic GABAB receptor-mediated network excitation in the medial prefrontal cortex of Tsc2+/- mice.

The TSC1 and TSC2 tumor suppressor genes control the activity of mechanistic target of rapamycin (mTOR) pathway. Elevated activity of this pathway in Tsc2+/- mouse model leads to reduction of postsynaptic GABAB receptor-mediated inhibition and hyperexcitability in the medial prefrontal cortex (mPFC). In this study, we asked whether presynaptic GABAB receptors (GABABRs) can compensate this shift of hyperexcitability. Experiments were performed in brain slices from adolescent wild-type (WT) and Tsc2+/- mice. Miniature and spontaneous postsynaptic currents (m/sPSCs) were recorded from layer 2/3 pyramidal neurons in mPFC using patch-clamp technique using a Cs+-based intrapipette solution. Presynaptic GABABRs were activated by baclofen (10 µM) or blocked by CGP55845 (1 µM). Independent on genotype, GABABR modulators bidirectionally change miniature excitatory postsynaptic current (mEPSC) frequency by about 10%, indicating presynaptic GABABR-mediated effects on glutamatergic transmission are comparable in both genotypes. In contrast, frequencies of both mIPSCs and sIPCSs were suppressed by baclofen stronger in Tsc2+/- neurons than in WT ones, whereas CGP55845 significantly increased (m/s)IPSC frequencies only in WT cells. Effects of baclofen and CGP55845 on the amplitudes of evoked (e)IPSCs confirmed these observations. These data indicate (1) that GABAergic synapses are inhibited by ambient GABA in WT but not in Tsc2+/- slices, and (2) that baclofen shifts the E/I ratio, determined as the ratio of (m/s)EPSC frequency to (m/s)IPSC frequency, towards excitation only in Tsc2+/- cells. This excitatory presynaptic GABABR-mediated action has to be taken into account for a possible medication of mental disorders using baclofen.

Optimal Organization of Functional Connectivity Networks for Segregation and Integration With Large-Scale Critical Dynamics in Human Brains.

The optimal organization for functional segregation and integration in brain is made evident by the "small-world" feature of functional connectivity (FC) networks and is further supported by the loss of this feature that has been described in many types of brain disease. However, it remains unknown how such optimally organized FC networks arise from the brain's structural constrains. On the other hand, an emerging literature suggests that brain function may be supported by critical neural dynamics, which is believed to facilitate information processing in brain. Though previous investigations have shown that the critical dynamics plays an important role in understanding the relation between whole brain structural connectivity and functional connectivity, it is not clear if the critical dynamics could be responsible for the optimal FC network configuration in human brains. Here, we show that the long-range temporal correlations (LRTCs) in the resting state fMRI blood-oxygen-level-dependent (BOLD) signals are significantly correlated with the topological matrices of the FC brain network. Using structure-dynamics-function modeling approach that incorporates diffusion tensor imaging (DTI) data and simple cellular automata dynamics, we showed that the critical dynamics could optimize the whole brain FC network organization by, e.g., maximizing the clustering coefficient while minimizing the characteristic path length. We also demonstrated with a more detailed excitation-inhibition neuronal network model that loss of local excitation-inhibition (E/I) balance causes failure of critical dynamics, therefore disrupting the optimal FC network organization. The results highlighted the crucial role of the critical dynamics in forming an optimal organization of FC networks in the brain and have potential application to the understanding and modeling of abnormal FC configurations in neuropsychiatric disorders.

Increased aperiodic gamma power in young boys with Fragile X Syndrome is associated with better language ability.

BACKGROUND: The lack of robust and reliable clinical biomarkers in Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, has limited the successful translation of bench-to-bedside therapeutics. While numerous drugs have shown promise in reversing synaptic and behavioral phenotypes in mouse models of FXS, none have demonstrated clinical efficacy in humans. Electroencephalographic (EEG) measures have been identified as candidate biomarkers as EEG recordings of both adults with FXS and mouse models of FXS consistently exhibit alterations in resting state and task-related activity. However, the developmental timing of these EEG differences is not known as thus far EEG studies have not focused on young children with FXS. Further, understanding how EEG differences are associated with core symptoms of FXS is crucial to successful use of EEG as a biomarker, and may improve our understanding of the disorder. METHODS: Resting-state EEG was collected from FXS boys with full mutation of Fmr1 (2.5-7 years old, n = 11) and compared with both age-matched (n = 12) and cognitive-matched (n = 12) typically developing boys. Power spectra (including aperiodic and periodic components) were compared using non-parametric cluster-based permutation testing. Associations between 30 and 50 Hz gamma power and cognitive, language, and behavioral measures were evaluated using Pearson correlation and linear regression with age as a covariate. RESULTS: FXS participants showed increased power in the beta/gamma range (~ 25-50 Hz) across multiple brain regions. Both a reduction in the aperiodic (1/f) slope and increase in beta/gamma periodic activity contributed to the significant increase in high-frequency power. Increased gamma power, driven by the aperiodic component, was associated with better language ability in the FXS group. No association was observed between gamma power and parent report measures of behavioral challenges, sensory hypersensitivities, or adaptive behaviors. LIMITATIONS: The study sample size was small, although comparable to other human studies in rare-genetic disorders. Findings are also limited to males in the age range studied. CONCLUSIONS: Resting-state EEG measures from this study in young boys with FXS identified similar increases in gamma power previously reported in adults and mouse models. The observed positive association between resting state aperiodic gamma power and language development supports hypotheses that alterations in some EEG measures may reflect ongoing compensatory mechanisms.

Activity labeling in vivo using CaMPARI2 reveals intrinsic and synaptic differences between neurons with high and low firing rate set points.

Neocortical pyramidal neurons regulate firing around a stable mean firing rate (FR) that can differ by orders of magnitude between neurons, but the factors that determine where individual neurons sit within this broad FR distribution are not understood. To access low- and high-FR neurons for ex vivo analysis, we used Ca2+- and UV-dependent photoconversion of CaMPARI2 in vivo to permanently label neurons according to mean FR. CaMPARI2 photoconversion was correlated with immediate early gene expression and higher FRs ex vivo and tracked the drop and rebound in ensemble mean FR induced by prolonged monocular deprivation. High-activity L4 pyramidal neurons had greater intrinsic excitability and recurrent excitatory synaptic strength, while E/I ratio, local output strength, and local connection probability were not different. Thus, in L4 pyramidal neurons (considered a single transcriptional cell type), a broad mean FR distribution is achieved through graded differences in both intrinsic and synaptic properties.

Haploinsufficiency of Tsc2 Leads to Hyperexcitability of Medial Prefrontal Cortex via Weakening of Tonic GABAB Receptor-mediated Inhibition.

Loss-of-function mutation in one of the tumor suppressor genes TSC1 or TSC2 is associated with several neurological and psychiatric diseases, including autism spectrum disorders (ASDs). As an imbalance between excitatory and inhibitory neurotransmission, E/I ratio is believed to contribute to the development of these disorders, we investigated synaptic transmission during the first postnatal month using the Tsc2+/- mouse model. Electrophysiological recordings were performed in acute brain slices of medial prefrontal cortex. E/I ratio at postnatal day (P) 15-19 is increased in Tsc2+/- mice as compared with wildtype (WT). At P25-30, facilitated GABAergic transmission reduces E/I ratio to the WT level, but weakening of tonic GABAB receptor (GABABR)-mediated inhibition in Tsc2+/- mice leads to hyperexcitability both at single cell and neuronal network level. Short (1 h) preincubation of P25-30 Tsc2+/- slices with baclofen restores the GABABR-mediated inhibition and reduces network excitability. Interestingly, the same treatment at P15-19 leads to weakening of GABABR-mediated inhibition. We hypothesize that a dysfunction of tonic GABABR-mediated inhibition might contribute to the development of ASD symptoms and suggest that GABABR activation within an appropriate time window may be considered as a therapeutic target in ASD.

Subanesthetic ketamine exerts antidepressant-like effects in adult rats exposed to juvenile stress.

Juvenile stress, like that caused by childhood maltreatment, is a significant risk factor for psychiatric disorders such as depression later in life. Recently, the antidepressant effect of ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist, has been widely investigated. However, little is known regarding its efficacy against depressive-like alterations caused by juvenile stress, which is clinically relevant in human depression. In the present study, we evaluated the antidepressant-like effect of ketamine in adult rats that had been subjected to juvenile stress. Depressive-like behavior was assessed using the forced swim test (FST), and electrophysiological and morphological alterations in the layer V pyramidal cells of the prelimbic cortex were examined using whole-cell patch-clamp recordings and subsequent recording-cell specific fluorescence imaging. We demonstrated that ketamine (10 mg/kg) attenuated the increased immobility time caused by juvenile stress in the FST, restored the diminished excitatory postsynaptic currents, and caused atrophic changes in the apical dendritic spines. Ketamine's effects reversing impaired excitatory/inhibitory ratio of postsynaptic currents were also revealed. These results indicated that ketamine could be effective in reversing the depression-like alterations caused by juvenile stress.

Modulation of Coordinated Activity across Cortical Layers by Plasticity of Inhibitory Synapses.

In the neocortex, synaptic inhibition shapes all forms of spontaneous and sensory evoked activity. Importantly, inhibitory transmission is highly plastic, but the functional role of inhibitory synaptic plasticity is unknown. In the mouse barrel cortex, activation of layer (L) 2/3 pyramidal neurons (PNs) elicits strong feedforward inhibition (FFI) onto L5 PNs. We find that FFI involving parvalbumin (PV)-expressing cells is strongly potentiated by postsynaptic PN burst firing. FFI plasticity modifies the PN excitation-to-inhibition (E/I) ratio, strongly modulates PN gain, and alters information transfer across cortical layers. Moreover, our LTPi-inducing protocol modifies firing of L5 PNs and alters the temporal association of PN spikes to γ-oscillations both in vitro and in vivo. All of these effects are captured by unbalancing the E/I ratio in a feedforward inhibition circuit model. Altogether, our results indicate that activity-dependent modulation of perisomatic inhibitory strength effectively influences the participation of single principal cortical neurons to cognition-relevant network activity.

Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models.

Distinct genetic forms of autism are hypothesized to share a common increase in excitation-inhibition (E-I) ratio in cerebral cortex, causing hyperexcitability and excess spiking. We provide a systematic test of this hypothesis across 4 mouse models (Fmr1-/y, Cntnap2-/-, 16p11.2del/+, Tsc2+/-), focusing on somatosensory cortex. All autism mutants showed reduced feedforward inhibition in layer 2/3 coupled with more modest, variable reduction in feedforward excitation, driving a common increase in E-I conductance ratio. Despite this, feedforward spiking, synaptic depolarization, and spontaneous spiking were largely normal. Modeling revealed that E and I conductance changes in each mutant were quantitatively matched to yield stable, not increased, synaptic depolarization for cells near spike threshold. Correspondingly, whisker-evoked spiking was not increased in vivo despite detectably reduced inhibition. Thus, elevated E-I ratio is a common circuit phenotype but appears to reflect homeostatic stabilization of synaptic drive rather than driving network hyperexcitability in autism.

Cross-Modal Reinstatement of Thalamocortical Plasticity Accelerates Ocular Dominance Plasticity in Adult Mice.

Plasticity of thalamocortical (TC) synapses is robust during early development and becomes limited in the adult brain. We previously reported that a short duration of deafening strengthens TC synapses in the primary visual cortex (V1) of adult mice. Here, we demonstrate that deafening restores NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of TC synapses onto principal neurons in V1 layer 4 (L4), which is accompanied by an increase in NMDAR function. In contrast, deafening did not recover long-term depression (LTD) at TC synapses. Potentiation of TC synapses by deafening is absent in parvalbumin-positive (PV+) interneurons, resulting in an increase in feedforward excitation to inhibition (E/I) ratio. Furthermore, we found that a brief duration of deafening adult mice recovers rapid ocular dominance plasticity (ODP) mainly by accelerating potentiation of the open-eye responses. Our results suggest that cross-modal sensory deprivation promotes adult cortical plasticity by specifically recovering TC-LTP and increasing the E/I ratio.

Loss of Synapse Repressor MDGA1 Enhances Perisomatic Inhibition, Confers Resistance to Network Excitation, and Impairs Cognitive Function.

Synaptopathies contributing to neurodevelopmental disorders are linked to mutations in synaptic organizing molecules, including postsynaptic neuroligins, presynaptic neurexins, and MDGAs, which regulate their interaction. The role of MDGA1 in suppressing inhibitory versus excitatory synapses is controversial based on in vitro studies. We show that genetic deletion of MDGA1 in vivo elevates hippocampal CA1 inhibitory, but not excitatory, synapse density and transmission. Furthermore, MDGA1 is selectively expressed by pyramidal neurons and regulates perisomatic, but not distal dendritic, inhibitory synapses. Mdga1-/- hippocampal networks demonstrate muted responses to neural excitation, and Mdga1-/- mice are resistant to induced seizures. Mdga1-/- mice further demonstrate compromised hippocampal long-term potentiation, consistent with observed deficits in spatial and context-dependent learning and memory. These results suggest that mutations in MDGA1 may contribute to cognitive deficits through altered synaptic transmission and plasticity by loss of suppression of inhibitory synapse development in a subcellular domain- and cell-type-selective manner.

Pupillary autonomic dysfunction in patients with ANCA-associated vasculitis.

OBJECTIVE: To assess autonomic function by infrared dynamic pupillometry in patients with ANCA-vasculitis (AAV) in correlation to autonomic symptoms, disease specific clinical parameters and cardiovascular reflex tests. METHODS: Patients with AAV and healthy controls underwent pupillometry at rest and after sympathetic stimulation (cold pressor test). Three parasympathetic parameters (amplitude, relative amplitude, maximum constriction velocity) and one sympathetic parameter (late dilatation velocity) were assessed. Results were correlated with clinical parameters, symptoms of autonomic dysfunction (COMPASS31 questionnaire), heart rate variability during deep breathing test and blood pressure response to pain. RESULTS: 23 patients and 18 age-matched controls were enrolled. Patients had a smaller amplitude (1.44 vs. 1.70 mm; p = 0.009) and a slower constriction velocity (4.15 vs. 4.71 mm/s; p = 0.028) at baseline and after sympathetic stimulation (1.47 vs. 1.81 mm, p = 0.001; 4.38 vs. 5.19 mm/s, p = 0.006, respectively). Relative amplitude was significantly smaller in patients after sympathetic stimulation (28.6 vs. 32.5%; p = 0.043), but not at baseline. There was no difference in sympathetic pupillary response between the groups. In patients, parasympathetic pupil response was correlated negatively with age and positively with parasympathetic cardiac response. After adjusting for age, no significant correlation was observed with clinical parameters. However, there was a trend towards a negative correlation with disease duration, vasculitis damage index and CRP. CONCLUSION: Patients with AAV exhibit parasympathetic pupillary autonomic dysfunction. Although correlations were weak and not significant, pupillary autonomic dysfunction is rather linked to chronic damage than to active inflammation or symptoms of autonomic dysfunction.

Reallocation of Olfactory Cajal-Retzius Cells Shapes Neocortex Architecture.

The neocortex undergoes extensive developmental growth, but how its architecture adapts to expansion remains largely unknown. Here, we investigated how early born Cajal-Retzius (CR) neurons, which regulate the assembly of cortical circuits, maintain a dense superficial distribution in the growing neocortex. We found that CR cell density is sustained by an activity-dependent importation of olfactory CR cells, which migrate into the neocortex after they have acted as axonal guidepost cells in the olfactory system. Furthermore, using mouse genetics, we showed that CR cell density severely affects the architecture of layer 1, a key site of input integration for neocortical networks, leading to an excitation/inhibition ratio imbalance. Our study reveals that neurons reenter migration several days after their initial positioning, thereby performing sequential developmental roles in olfactory cortex and neocortex. This atypical process is essential to regulate CR cell density during growth, which in turn ensures the correct wiring of neocortical circuitry. VIDEO ABSTRACT.

Differential susceptibility of cortical and subcortical inhibitory neurons and astrocytes in the long term following diffuse traumatic brain injury.

Long-term diffuse traumatic brain injury (dTBI) causes neuronal hyperexcitation in supragranular layers in sensory cortex, likely through reduced inhibition. Other forms of TBI affect inhibitory interneurons in subcortical areas but it is unknown if this occurs in cortex, or in any brain area in dTBI. We investigated dTBI effects on inhibitory neurons and astrocytes in somatosensory and motor cortex, and hippocampus, 8 weeks post-TBI. Brains were labeled with antibodies against calbindin (CB), parvalbumin (PV), calretinin (CR) and neuropeptide Y (NPY), and somatostatin (SOM) and glial fibrillary acidic protein (GFAP), a marker for astrogliosis during neurodegeneration. Despite persistent behavioral deficits in rotarod performance up to the time of brain extraction (TBI = 73.13 ± 5.23% mean ± SEM, Sham = 92.29 ± 5.56%, P < 0.01), motor cortex showed only a significant increase, in NPY neurons in supragranular layers (mean cells/mm2 ± SEM, Sham = 16 ± 0.971, TBI = 25 ± 1.51, P = 0.001). In somatosensory cortex, only CR+ neurons showed changes, being decreased in supragranular (TBI = 19 ± 1.18, Sham = 25 ± 1.10, P < 0.01) and increased in infragranular (TBI = 28 ± 1.35, Sham = 24 ± 1.07, P < 0.05) layers. Heterogeneous changes were seen in hippocampal staining: CB+ decreased in dentate gyrus (TBI = 2 ± 0.382, Sham = 4 ± 0.383, P < 0.01), PV+ increased in CA1 (TBI = 39 ± 1.26, Sham = 33 ± 1.69, P < 0.05) and CA2/3 (TBI = 26 ± 2.10, Sham = 20 ± 1.49, P < 0.05), and CR+ decreased in CA1 (TBI = 10 ± 1.02, Sham = 14 ± 1.14, P < 0.05). Astrogliosis significantly increased in corpus callosum (TBI = 6.7 ± 0.69, Sham = 2.5 ± 0.38; P = 0.007). While dTBI effects on inhibitory neurons appear region- and type-specific, a common feature in all cases of decrease was that changes occurred in dendrite targeting interneurons involved in neuronal integration. J. Comp. Neurol. 524:3530-3560, 2016. © 2016 Wiley Periodicals, Inc.

Interneuron Transcriptional Dysregulation Causes Frequency-Dependent Alterations in the Balance of Inhibition and Excitation in Hippocampus.

Circuit dysfunction in complex brain disorders such as schizophrenia and autism is caused by imbalances between inhibitory and excitatory synaptic transmission (I/E). Short-term plasticity differentially alters responses from excitatory and inhibitory synapses, causing the I/E ratio to change as a function of frequency. However, little is known about I/E ratio dynamics in complex brain disorders. Transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, is a consistent pathophysiological feature of schizophrenia. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator that in hippocampus is highly concentrated in inhibitory interneurons and regulates parvalbumin transcription. Here, we used PGC-1α(-/-) mice to investigate effects of interneuron transcriptional dysregulation on the dynamics of the I/E ratio at the synaptic and circuit level in hippocampus. We find that loss of PGC-1α increases the I/E ratio onto CA1 pyramidal cells in response to Schaffer collateral stimulation in slices from young adult mice. The underlying mechanism is enhanced basal inhibition, including increased inhibition from parvalbumin interneurons. This decreases the spread of activation in CA1 and dramatically limits pyramidal cell spiking, reducing hippocampal output. The I/E ratio and CA1 output are partially restored by paired-pulse stimulation at short intervals, indicating frequency-dependent effects. However, circuit dysfunction persists, indicated by alterations in kainate-induced gamma oscillations and impaired nest building. Together, these results show that transcriptional dysregulation in hippocampal interneurons causes frequency-dependent alterations in I/E ratio and circuit function, suggesting that PGC-1α deficiency in psychiatric and neurological disorders contributes to disease by causing functionally relevant alterations in I/E balance. SIGNIFICANCE STATEMENT: Alteration in the inhibitory and excitatory synaptic transmission (I/E) balance is a fundamental principle underlying the circuit dysfunction observed in many neuropsychiatric and neurodevelopmental disorders. The I/E ratio is dynamic, continuously changing because of synaptic short-term plasticity. We show here that transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, causes frequency-dependent alterations in the I/E ratio and in circuit function in hippocampus. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α-deficient) mice have enhanced inhibition in CA1, the opposite of what is seen in cortex. This study fills an important gap in current understanding of how changes in inhibition in complex brain disorders affect I/E dynamics, leading to region-specific circuit dysfunction and behavioral impairment. This study also provides a conceptual framework for analyzing the effects of short-term plasticity on the I/E balance in disease models.

Long-lasting changes in neural networks to compensate for altered nicotinic input.

The nervous system must balance excitatory and inhibitory input to constrain network activity levels within a proper dynamic range. This is a demanding requirement during development, when networks form and throughout adulthood as networks respond to constantly changing environments. Defects in the ability to sustain a proper balance of excitatory and inhibitory activity are characteristic of numerous neurological disorders such as schizophrenia, Alzheimer's disease, and autism. A variety of homeostatic mechanisms appear to be critical for balancing excitatory and inhibitory activity in a network. These are operative at the level of individual neurons, regulating their excitability by adjusting the numbers and types of ion channels, and at the level of synaptic connections, determining the relative numbers of excitatory versus inhibitory connections a neuron receives. Nicotinic cholinergic signaling is well positioned to contribute at both levels because it appears early in development, extends across much of the nervous system, and modulates transmission at many kinds of synapses. Further, it is known to influence the ratio of excitatory-to-inhibitory synapses formed on neurons during development. GABAergic inhibitory neurons are likely to be key for maintaining network homeostasis (limiting excitatory output), and nicotinic signaling is known to prominently regulate the activity of several GABAergic neuronal subtypes. But how nicotinic signaling achieves this and how networks may compensate for the loss of such input are important questions remaining unanswered. These issues are reviewed.