Gamma Rhythms Link Prefrontal Interneuron Dysfunction with Cognitive Inflexibility in Dlx5/6+/− Mice

Abstract

SUMMARY Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ~30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for Dlx5/6, which regulate GABAergic interneuron development. In Dlx5/6+/− mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked γ oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at γ-frequencies restored cognitive flexibility in adult Dlx5/6+/− mice. These pro-cognitive effects were frequency-specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven gamma oscillations in cognitive domains at the core of schizophrenia.

Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

“…Network hyperexcitability and epileptiform events have been observed in most mouse models of AD (Palop et al, 2007, 2011; Busche et al, 2008; Palop and Mucke, 2009; Harris et al, 2010; Roberson et al, 2011; Yan et al, 2012; Busche and Konnerth, 2016) and in AD patients using high resolution recordings (Lam et al, 2017). Hypersynchronous network activities have been shown to emerge during reduced gamma oscillation, which is a rhythm that depends on the activities of fast-spiking PV INs and contributes to cognitive functions (Cardin et al, 2009; Sohal et al, 2009; Buzsáki and Wang, 2012; Sohal, 2012; Cho et al, 2015). Specifically, PV IN defects due to a reduced expression of voltage-gated sodium channels Nav1.1 were found in hAPPJ20 mice, and reversing the Nav1.1 reduction by Nav1.1-BAC bacterial rescued PV IN synaptic currents and gamma oscillations and reduced network hypersynchrony and memory deficits in these mice (Verret et al, 2012).…”

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

“…Moreover, using optogenetic tools in animals, it has recently been demonstrated that gamma oscillatory activity in the pre‐frontal cortex controlled by FSIs is important for cognitive performance (Cho et al . 2015, Kim et al . 2016).…”

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…Dlx5/6(+/-) mice show a reduced cognitive flexibility that seemingly results from an abnormal pattern of γ rhythms caused by abnormalities in GABAergic interneurons; this phenotype recapitulates some clinical findings in SZ patients [Cho et al, 2015]. During language processing, γ rhythms are hypothesized to generate syntactic objects before β holds them in memory and they also contributes to lexical processing [see Murphy, 2015, for details].…”