Abstract
BackgroundOscillations in neuronal activity tie the pathophysiology of schizophrenia to alterations in local processing and large-scale coordination, and these alterations in turn can lead to the cognitive and perceptual disturbances observed in schizophrenia. Here, we focus on the dual role of fast-spiking, parvalbumin (PV+) networks in the generation of gamma oscillations and critical periods of brain plasticity.MethodsWe generated a mouse model of reduced recurrent inhibition only within local PV+ cell networks by selective removal of GABAA receptor alpha1 subunits (PV-α1 KO mice). Electroencephalography (EEG), PV+ immunohistochemistry, perineuronal net (PNN) labeling and redox balance were compared to cortical measures of brain plasticity (loss of visual acuity, formation of preference behaviors) that are typically limited to a critical period early in life.ResultsPV-α1 KO mice exhibit chronically enhanced gamma-oscillations and extended juvenile forms of cortical plasticity into adulthood. Acute pharmacological suppression of excitatory input restored E-I balance onto these disinhibited PV+ cells and returned baseline EEG power to normal levels, preventing the extended plasticity. Enhanced gamma oscillations were further found to compromise the integrity of perineuronal nets (PNNs) surrounding PV+ cells, elevating oxidative stress and the turnover of metallopeptidases and structural components of the PNN. All of these aspects were also reversed by pharmacological dampening of excitation onto PV+ cells.DiscussionCortical gamma oscillations are associated with plasticity and cognition. Our results provide a cellular explanation of how elevated gamma oscillations may promote ectopic brain plasticity by regulating the extracellular matrix which normally stabilizes cortical circuitry. These results carry broad implications for subjects at-risk for schizophrenia who exhibit heightened gamma oscillations prior to psychosis onset (see talk by P Uhlhaas).
Highlights
He will show that alterations in gamma-band oscillations are present prior to the onset of schizophrenia in at-risk individuals and related to aberrant E-I balance parameters revealed by MRS-measured levels of GABA and glutamate
Oscillations in neuronal activity tie the pathophysiology of schizophrenia to alterations in local processing and large-scale coordination, and these alterations in turn can lead to the cognitive and perceptual disturbances observed in schizophrenia
Electroencephalography (EEG), PV+ immunohistochemistry, perineuronal net (PNN) labeling and redox balance were compared to cortical measures of brain plasticity that are typically limited to a critical period early in life
Summary
Evidence is accumulating that core features of schizophrenia (SCH) may arise from a fundamental disturbance in the cellular balance of excitation and inhibition (E-I balance) within neural circuitry. Lawrence Kegeles will present simultaneous EEG and proton MRS measurements of glutamate and GABA during ketamine administration in healthy young adults These data will be compared with the same modalities acquired in individuals at clinical high risk and patients with SCH, showing disturbed delta and gamma band power and altered E-I balance despite homeostatic rebalancing of glutamate and GABA. Peter Uhlhaas will summarize evidence from EEG/MEG data examining the potential role of neural oscillations in the pathophysiology of schizophrenia He will show that alterations in gamma-band oscillations are present prior to the onset of schizophrenia in at-risk individuals and related to aberrant E-I balance parameters revealed by MRS-measured levels of GABA and glutamate. Developmental data on the maturation of neural oscillations suggests that the transition from adolescence to adulthood is a sensitive period for modifications in neuronal dynamics that could potentially explain the manifestation of psychosis during this period
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