Hippocampal–prefrontal coherence mediates working memory and selective attention at distinct frequency bands and provides a causal link between schizophrenia and its risk gene GRIA1

Abstract

Increased fronto-temporal theta coherence and failure of its stimulus-specific modulation have been reported in schizophrenia, but the psychological correlates and underlying neural mechanisms remain elusive. Mice lacking the putative schizophrenia risk gene GRIA1 ( Gria1 –/– ), which encodes GLUA1, show strongly impaired spatial working memory and elevated selective attention owing to a deficit in stimulus-specific short-term habituation. A failure of short-term habituation has been suggested to cause an aberrant assignment of salience and thereby psychosis in schizophrenia. We recorded hippocampal–prefrontal coherence while assessing spatial working memory and short-term habituation in these animals, wildtype (WT) controls, and Gria1 –/– mice in which GLUA1 expression was restored in hippocampal subfields CA2 and CA3. We found that beta (20–30 Hz) and low-gamma (30–48 Hz) frequency coherence could predict working memory performance, whereas—surprisingly—theta (6–12 Hz) coherence was unrelated to performance and largely unaffected by genotype in this task. In contrast, in novel environments, theta coherence specifically tracked exploration-related attention in WT mice, but was strongly elevated and unmodulated in Gria1 -knockouts, thereby correlating with impaired short-term habituation. Strikingly, reintroduction of GLUA1 selectively into CA2/CA3 restored abnormal short-term habituation, theta coherence, and hippocampal and prefrontal theta oscillations. Although local oscillations and coherence in other frequency bands (beta, gamma), and theta-gamma cross-frequency coupling also showed dependence on GLUA1, none of them correlated with short-term habituation. Therefore, sustained elevation of hippocampal–prefrontal theta coherence may underlie a failure in regulating novelty-related selective attention leading to aberrant salience, and thereby represents a mechanistic link between GRIA1 and schizophrenia.

Lack of redundancy between electrophysiological measures of long-range neuronal communication

“…Recordings from all sites were made during a 10 min test of noveltyinduced locomotor activity which confirmed the strongly elevated behavioural activity and failure of its short-term habituation over time, as observed in Gria1 -/mice before (Fig. 1B, C; [42]). After experiments were completed, the placement of electrodes were evaluated through electrolytic lesion sites and misplaced electrodes were excluded from the dataset; data from the MD was disregarded for most of the subsequent analysis because of the low number of animals with accurate placements.…”

“…To this end we recorded data during a simple behavioural assay -novelty-induced locomotion and its habituation over time -in Gria1 -/-(KO, knockout) mice and their littermate controls. We have recently shown, that the Gria1-KO model, which is related to schizophrenia, shows profound and state-dependent aberrations of hippocampal-prefrontal coupling in this task [42]. We focused on the most widely used connectivity measurescoherence, ImC, wPLI, cross-amplitude coupling, parametric GC, SPC and SPC-related…”

“…After experiments were completed, the placement of electrodes were evaluated through electrolytic lesion sites and misplaced electrodes were excluded from the dataset; data from the MD was disregarded for most of the subsequent analysis because of the low number of animals with accurate placements. In accordance with our previous study in this mouse line [42], we recorded and analysed all data as referenced to the ground screw above the cerebellum by default and used the data from the frontal reference screw for a separate analysis (displayed in Fig. 7).…”

<p>Increased Plasma Kynurenic Acid Levels are Associated with Impaired Attention/Vigilance and Social Cognition in Patients with Schizophrenia</p>

“…Cognitive deficit is the key feature of schizophrenia (SCZ), and includes a range of domain deficits such as executive function, learning, memory, attention, and social cognition. [1][2][3][4] These may emerge long before illness onset and remain unchanged with improvement of clinical symptoms in SCZ patients. 5 Cognitive impairments are correlated with poor clinical outcome and rehabilitation of social function.…”

Visualizing synaptic plasticity in vivo by large-scale imaging of endogenous AMPA receptors

“…To further validate our SEP-GluA1 knockin line, we conducted a battery of behavioral experiments using homozygous SEP-GluA1 mice (9 females and 7 males) and WT (9 females and 9 males) littermates (aged 6-10 weeks), as GluA1 knockout mice show deficits in several behaviors, including locomotor activity, anxiety, and spatial memory (Bannerman et al, 2004;Boerner et al, 2017;Bygrave et al, 2019;Sanderson et al, 2007). We assessed locomotor activity by placing animals in an open arena and measuring the number of beam breaks during a 30-minute session.…”