Impaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective

Krystal, John H.; Antičević, Alan; Yang, Genevieve; Drăgoi, George; Driesen, Naomi; Wang, Xiao Jing; Murray, John D.

doi:10.1016/j.biopsych.2017.01.004

Cited by 171 publications

(145 citation statements)

References 156 publications

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“…Dendritic inhibition is thought to be crucial for the context-dependent gating of inputs 42 . Dysregulation of dendritic inhibition is therefore expected to allow aberrant sensory inputs into the prefrontal cortex, thereby disorganize the taskspecific activity patterns of prefrontal cortical neurons 43 . Experimentally, this matches with our finding of ketamine-induced prefrontal cortical hyperconnectivity.…”

Section: Discussionmentioning

confidence: 99%

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Ali

Gerhard

Sweasy

et al. 2019

Preprint

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A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and then more sustained antidepressant effects. A key targeted brain region is the prefrontal cortex, and the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine may act preferentially on GABAergic neurons. However, cortical GABAergic neurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that administration of ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine's actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine. disinhibition and calcium elevations in dendritic spines are important components of ketamine's actions on the prefrontal cortex. Results Subanesthetic ketamine modifies prefrontal cortical activity in a cell-type-specific mannerWe performed two-photon microscopy on awake, head-fixed mice (Fig. 1a), targeting the Cg1/M2 sub-regions of the medial prefrontal cortex (Fig. 1b). Initially, while mice were headfixed under the two-photon microscope, we recorded body motion using an infrared camera. This was because systemic administration of subanesthetic ketamine induces hyperlocomotion in rodents 15 , and we wanted to avoid movement as a confound in our imaging experiments. We observed that ketamine (10 mg/kg, s.c.) increased body motion but only transiently, and therefore limited all of our data collection to 30 -60 minutes post-injection (Fig. 1c, d). For calcium imaging, we used AAV1-CamKII-GCaMP6f-WPRE-SV40 to express the calcium-sensitive fluorescent protein GCaMP6f in pyramidal neurons in Cg1/M2, and imaged spontaneous fluorescence transients from the awake mouse (Fig. 1e). From the fluorescence transients, we detected calcium events using a peeling method based on template matching 16 . Ketamine (10 mg/kg, s.c.) increased the rate of spontaneous calcium events in pyramidal neuron cell bodies in layer 2/3 (200 -400 µm from the dura) (ketamine: 23.7 ± 2.1%, saline: 9.4 ± 1.9%, relative to pre-injection, mean ± s.e.m.; P = 3 x 10 -8 , two-sample t-test; Fig. 1f, g). These somatic calcium transients have been shown to directly relate to the firing rate of cortical neurons 17, 18 , therefore the elevated calcium event rates reflect hyperactivity of pyramidal neurons, consistent with previous reports 12,19 . To characterize the effect of ketamine ...

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Section: Discussionmentioning

confidence: 99%

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Ali

Gerhard

Sweasy

et al. 2019

Preprint

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“…[194]) and provided interpretations that incorporate advances in our understanding of how the brain codes information. For example, Krystal et al, [49] described the critical role of balance between glutamatergic excitation and GABAergic inhibition in generating finely-tuned neural circuits that efficiently represent information. They postulated that genetically-driven deficits in glutamatergic synaptic development may ultimately lead to impaired tuning of neural circuits; imprecise representations of information; and cognitive symptoms, delusions, and hallucinations.…”

Section: Pathways From Impaired Synaptic Plasticity To Psychosismentioning

confidence: 99%

“…Notably, PV interneurons in schizophrenia patients were recently found to receive fewer synaptic inputs from excitatory neurons than in control subjects, with excitatory input reductions predicting the downregulation of activity-dependent gene products in PV interneurons [47]. Thus, although reduced PV interneuron function and PNN expression could directly contribute to cortical disinhibition and circuit level dysfunction in schizophrenia [46,48,49], changes in PV interneurons and PNNs might arise during development as compensatory responses to reduced pyramidal cell activity.…”

Section: Figurementioning

confidence: 99%

Mapping the Consequences of Impaired Synaptic Plasticity in Schizophrenia through Development: An Integrative Model for Diverse Clinical Features

Forsyth

Lewis

2017

Trends in Cognitive Sciences

122

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Schizophrenia is associated with alterations in sensory, motor, and cognitive functions that emerge prior to psychosis-onset; identifying pathogenic processes that can account for this multi-faceted phenotype remains a challenge. Accumulating evidence suggests that synaptic plasticity is impaired in schizophrenia. Given the role of synaptic plasticity in learning, memory, and neural circuit maturation, impaired plasticity may underlie many features of the schizophrenia syndrome. Here, we summarize the neurobiology of synaptic plasticity, review evidence that plasticity is impaired in schizophrenia, and explore a framework in which impaired synaptic plasticity interacts with brain maturation to yield the emergence of sensory, motor, cognitive, and psychotic features at different times during development in schizophrenia. Key gaps in the literature and future directions for testing this framework are discussed.

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“…Our multiscale modeling study suggests that network synchronization and pyramidal neuronal excitability are potential dynamical targets for the treatment of cognitive symptoms and information processing deficits in schizophrenia. We showed how manipulating multiple molecular elements in a multi-target pharmacotherapy approach explains some of the inverted-U shaped phenomena seen in schizophrenia [43]. Multi-target pharmacotherapy is necessarily already used in schizophrenia treatment.…”

Section: Clinical Relevancementioning

confidence: 96%

In silicohippocampal modeling for multi-target pharmacotherapy in schizophrenia

Sherif

Neymotin

Lytton

2019

Preprint

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Background: Treatment of schizophrenia has had limited success in treating core cognitive symptoms. The evidence of multi-gene involvement suggests that multi-target therapy may be needed. Meanwhile, the complexity of schizophrenia pathophysiology and psychopathology, coupled with the species-specificity of much of the symptomatology, places limits on analysis via animal models, in vitro assays, and patient assessment. Multiscale computer modeling complements these traditional modes of study.Methods: Using a hippocampal CA3 computer model with 1200 neurons, we examined the effects of alterations in NMDAR, HCN (I h current), and GABA A R on information flow (measured with normalized transfer entropy), and in gamma activity in local field potential (LFP).Results: Altering NMDARs, GABA A R, I h , individually or in combination, modified information flow in an inverted-U shape manner, with information flow reduced at low and high levels of these parameters. The strong information flow seen at the peaks were associated with an intermediate level of synchrony, seen as an intermediate level of gamma activity in the LFP, and an intermediate level of pyramidal cell excitability.Conclusions: Our results are consistent with the idea that overly low or high gamma power is associated with pathological information flow and information processing. These data suggest the need for careful titration of schizophrenia pharmacotherapy to avoid extremes that alter information flow in different ways. These results also identify gamma power as a potential biomarker for monitoring pathology and multi-target pharmacotherapy.

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Impaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective

Cited by 171 publications

References 156 publications

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Mapping the Consequences of Impaired Synaptic Plasticity in Schizophrenia through Development: An Integrative Model for Diverse Clinical Features

In silicohippocampal modeling for multi-target pharmacotherapy in schizophrenia

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