Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders

O’Donnell, Cian; Gonçalves, J. Tiago; Portera‐Cailliau, Carlos; Sejnowski, Terrence J.

doi:10.7554/elife.26724

Cited by 53 publications

(26 citation statements)

References 75 publications

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“…It is well established that the balance between excitation and inhibition is of paramount importance for the correct function of the nervous system. Indeed, many neurodevelopmental brain disorders may arise from imbalances in excitatory and inhibitory brain circuitry, including schizophrenia and autism ( O’Donnell et al, 2017 ). Na + , K + , and Ca 2+ ion channels are the proteins studied most extensively in the shaping of neuron excitability, particularly since the pharmacology of Cl - channels has hindered the better understanding of their physiological importance.…”

Section: Discussionmentioning

confidence: 99%

A Calcium-Dependent Chloride Current Increases Repetitive Firing in Mouse Sympathetic Neurons

et al. 2018

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Ca2+-activated ion channels shape membrane excitability in response to elevations in intracellular Ca2+. The most extensively studied Ca2+-sensitive ion channels are Ca2+-activated K+ channels, whereas the physiological importance of Ca2+-activated Cl- channels has been poorly studied. Here we show that a Ca2+-activated Cl- currents (CaCCs) modulate repetitive firing in mouse sympathetic ganglion cells. Electrophysiological recording of mouse sympathetic neurons in an in vitro preparation of the superior cervical ganglion (SCG) identifies neurons with two different firing patterns in response to long depolarizing current pulses (1 s). Neurons classified as phasic (Ph) made up 67% of the cell population whilst the remainders were tonic (T). When a high frequency train of spikes was induced by intracellular current injection, SCG sympathetic neurons reached an afterpotential mainly dependent on the ratio of activation of two Ca2+-dependent currents: the K+ [IK(Ca)] and CaCC. When the IK(Ca) was larger, an afterhyperpolarization was the predominant afterpotential but when the CaCC was larger, an afterdepolarization (ADP) was predominant. These afterpotentials can be observed after a single action potential (AP). Ph and T neurons had similar ADPs and hence, the CaCC does not seem to determine the firing pattern (Ph or T) of these neurons. However, inhibition of Ca2+-activated Cl- channels with anthracene-9′-carboxylic acid (9AC) selectively inhibits the ADP, reducing the firing frequency and the instantaneous frequency without affecting the characteristics of single- or first-spike firing of both Ph and T neurons. Furthermore, we found that the CaCC underlying the ADP was significantly larger in SCG neurons from males than from females. Furthermore, the CaCC ANO1/TMEM16A was more strongly expressed in male than in female SCGs. Blocking ADPs with 9AC did not modify synaptic transmission in either Ph or T neurons. We conclude that the CaCC responsible for ADPs increases repetitive firing in both Ph and T neurons, and it is more relevant in male mouse sympathetic ganglion neurons.

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Section: Discussionmentioning

confidence: 99%

A Calcium-Dependent Chloride Current Increases Repetitive Firing in Mouse Sympathetic Neurons

et al. 2018

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“…The use of a single unit to simulate all feedforward inhibition is obviously not biologically realistic, and evidence suggests that models with a single inhibitory input cannot capture the true complexity of disruptions to EI balance that occur in some neurological disorders [ 59 ]. Moreover, the effects of manipulating inhibition may depend on detailed excitatory-inhibitory interactions [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

Irrelevance by inhibition: Learning, computation, and implications for schizophrenia

2018

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Symptoms of schizophrenia may arise from a failure of cortical circuits to filter-out irrelevant inputs. Schizophrenia has also been linked to disruptions in cortical inhibitory interneurons, consistent with the possibility that in the normally functioning brain, these cells are in some part responsible for determining which sensory inputs are relevant versus irrelevant. Here, we develop a neural network model that demonstrates how the cortex may learn to ignore irrelevant inputs through plasticity processes affecting inhibition. The model is based on the proposal that the amount of excitatory output from a cortical circuit encodes the expected magnitude of reward or punishment (“relevance”), which can be trained using a temporal difference learning mechanism acting on feedforward inputs to inhibitory interneurons. In the model, irrelevant and blocked stimuli drive lower levels of excitatory activity compared with novel and relevant stimuli, and this difference in activity levels is lost following disruptions to inhibitory units. When excitatory units are connected to a competitive-learning output layer with a threshold, the relevance code can be shown to “gate” both learning and behavioral responses to irrelevant stimuli. Accordingly, the combined network is capable of recapitulating published experimental data linking inhibition in frontal cortex with fear learning and expression. Finally, the model demonstrates how relevance learning can take place in parallel with other types of learning, through plasticity rules involving inhibitory and excitatory components, respectively. Altogether, this work offers a theory of how the cortex learns to selectively inhibit inputs, providing insight into how relevance-assignment problems may emerge in schizophrenia.

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“…Moreover, pharmacological compounds that modulate the GABA system have been tested for therapeutic efficacy in mouse models, and clinical trials are currently ongoing ( Braat and Kooy, 2015 ). However, a recent theoretical study proposed that a simple unidimensional E/I imbalance model cannot fully account for the aberrant neural circuit activity in Fmr1 KO mice ( Gonçalves et al, 2013 ; O’Donnell et al, 2017 ), implying that restoration of E/I balance by direct modulation of GABA signaling alone may be insufficient for some symptoms or forms of ASD.…”

Section: Serotonin-mediated E/i Rebalancing As a Potential Therapeutimentioning

confidence: 99%

“…In vivo calcium imaging can simultaneously record the activity of a large, dense population of neurons. The large datasets obtained with this technique are useful for testing the validity of theoretical models, and such a combined optical and theoretical approach may yield alternative theoretical models regarding the etiology of disorders ( O’Donnell et al, 2017 ).…”

Section: Conclusion and Outlook: Lessons From In Vivomentioning

confidence: 99%

Common Defects of Spine Dynamics and Circuit Function in Neurodevelopmental Disorders: A Systematic Review of Findings From in Vivo Optical Imaging of Mouse Models

et al. 2018

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In vivo optical imaging is a powerful tool for revealing brain structure and function at both the circuit and cellular levels. Here, we provide a systematic review of findings obtained from in vivo imaging studies of mouse models of neurodevelopmental disorders, including the monogenic disorders fragile X syndrome, Rett syndrome, and Angelman syndrome, which are caused by genetic abnormalities of FMR1, MECP2, and UBE3A, as well as disorders caused by copy number variations (15q11-13 duplication and 22q11.2 deletion) and BTBR mice as an inbred strain model of autism spectrum disorder (ASD). Most studies visualize the structural and functional responsiveness of cerebral cortical neurons to sensory stimuli and the developmental and experience-dependent changes in these responses as a model of brain functions affected by these disorders. The optical imaging techniques include two-photon microscopy of fluorescently labeled dendritic spines or neurons loaded with fluorescent calcium indicators and macroscopic imaging of cortical activity using calcium indicators, voltage-sensitive dyes or intrinsic optical signals. Studies have revealed alterations in the density, stability, and turnover of dendritic spines, aberrant cortical sensory responses, impaired inhibitory function, and concomitant failure of circuit maturation as common causes for neurological deficits. Mechanistic hypotheses derived from in vivo imaging also provide new directions for therapeutic interventions. For instance, it was recently demonstrated that early postnatal administration of a selective serotonin reuptake inhibitor (SSRI) restores impaired cortical inhibitory function and ameliorates the aberrant social behaviors in a mouse model of ASD. We discuss the potential use of SSRIs for treating ASDs in light of these findings.

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Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders

Cited by 53 publications

References 75 publications

A Calcium-Dependent Chloride Current Increases Repetitive Firing in Mouse Sympathetic Neurons

A Calcium-Dependent Chloride Current Increases Repetitive Firing in Mouse Sympathetic Neurons

Irrelevance by inhibition: Learning, computation, and implications for schizophrenia

Common Defects of Spine Dynamics and Circuit Function in Neurodevelopmental Disorders: A Systematic Review of Findings From in Vivo Optical Imaging of Mouse Models

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