Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice.

A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of SCZ, and underscore the utility of Grin2a-deficient mice as a genetic model of SCZ.

Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients.

Schizophrenia is a heterogeneous psychiatric disorder with a strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function mutations in GRIN2A (aka GluN2A or NR2A, encoding the NMDA receptor subunit 2A) and AKAP11 (A-Kinase Anchoring Protein 11). AKAP11 and GRIN2A mutations are also associated with bipolar disorder [2], and epilepsy and developmental delay/intellectual disability [1, 3, 4], respectively. Accessible in both humans and rodents, electroencephalogram (EEG) recordings offer a window into brain activity and display abnormal features in schizophrenia patients. Does loss of Grin2a or Akap11 in mice also result in EEG abnormalities? We monitored EEG in heterozygous and homozygous knockout Grin2a and Akap11 mutant mice compared with their wild-type littermates, at 3- and 6-months of age, across the sleep/wake cycle and during auditory stimulation protocols. Grin2a and Akap11 mutants exhibited increased resting gamma power, attenuated auditory steady-state responses (ASSR) at gamma frequencies, and reduced responses to unexpected auditory stimuli during mismatch negativity (MMN) tests. Sleep spindle density was reduced in a gene dose-dependent manner in Akap11 mutants, whereas Grin2a mutants showed increased sleep spindle density. The EEG phenotypes of Grin2a and Akap11 mutant mice show a variety of abnormal features that overlap considerably with human schizophrenia patients, reflecting systems-level changes caused by Grin2a and Akap11 deficiency. These neurophysiologic findings further substantiate Grin2a and Akap11 mutants as genetic models of schizophrenia and identify potential biomarkers for stratification of schizophrenia patients.

The function of groups of neurons changes from moment to moment.

Modern techniques that enable identification and targeted manipulation of neuron groups are frequently used to bolster theories that attribute specific behavioral functions to specific neuron types. These same techniques can also be used, however, to highlight limitations of such attribution, and to develop the argument that the question "what is the function of these neurons?" is ill-posed in the absence of temporal and network constraints. Here we do this, first reviewing evidence that neural responses are dynamic at multiple time scales, making the point that such changes in firing rates imply changes in what the neuron is doing. Studies involving brief perturbations of neural populations confirm this point, showing that the functions in which these populations participate change across seconds and even milliseconds. Based on these studies, we suggest that it is inappropriate to assign function to sets of neurons without contextualizing that assignment to specific times and network conditions.

Refinement and Reactivation of a Taste-Responsive Hippocampal Network.

Animals need to remember the locations of nourishing and toxic food sources for survival, a fact that necessitates a mechanism for associating taste experiences with particular places. We have previously identified such responses within hippocampal place cells [1], the activity of which is thought to aid memory-guided behavior by forming a mental map of an animal's environment that can be reshaped through experience [2-7]. It remains unknown, however, whether taste responsiveness is intrinsic to a subset of place cells or emerges as a result of experience that reorganizes spatial maps. Here, we recorded from neurons in the dorsal CA1 region of rats running for palatable tastes delivered via intra-oral cannulae at specific locations on a linear track. We identified a subset of taste-responsive cells that, even prior to taste exposure, had larger place fields than non-taste-responsive cells overlapping with stimulus delivery zones. Taste-responsive cells' place fields then contracted as a result of taste experience, leading to a stronger representation of stimulus delivery zones on the track. Taste-responsive units exhibited increased sharp-wave ripple co-activation during the taste delivery session and subsequent rest periods, which correlated with the degree of place field contraction. Our results reveal that novel taste experience evokes responses within a preconfigured network of taste-responsive hippocampal place cells with large fields, whose spatial representations are refined by sensory experience to signal areas of behavioral salience. This represents a possible mechanism by which animals identify and remember locations where ecologically relevant stimuli are found within their environment.

Interaction of Taste and Place Coding in the Hippocampus.

An animal's survival depends on finding food and the memory of food and contexts are often linked. Given that the hippocampus is required for spatial and contextual memory, it is reasonable to expect related coding of space and food stimuli in hippocampal neurons. However, relatively little is known about how the hippocampus responds to tastes, the most central sensory property of food. In this study, we examined the taste-evoked responses and spatial firing properties of single units in the dorsal CA1 hippocampal region as male rats received a battery of taste stimuli differing in both chemical composition and palatability within a specific spatial context. We identified a subset of hippocampal neurons that responded to tastes, some of which were place cells. These taste and place responses had a distinct interaction: taste-responsive cells tended to have less spatially specific firing fields and place cells only responded to tastes delivered inside their place field. Like neurons in the amygdala and lateral hypothalamus, hippocampal neurons discriminated between tastes predominantly on the basis of palatability, with taste selectivity emerging concurrently with palatability-relatedness; these responses did not reflect movement or arousal. However, hippocampal taste responses emerged several hundred milliseconds later than responses in other parts of the taste system, suggesting that the hippocampus does not influence real-time taste decisions, instead associating the hedonic value of tastes with a particular context. This incorporation of taste responses into existing hippocampal maps could be one way that animals use past experience to locate food sources.SIGNIFICANCE STATEMENT Finding food is essential for animals' survival and taste and context memory are often linked. Although hippocampal responses to space and contexts have been well characterized, little is known about how the hippocampus responds to tastes. Here, we identified a subset of hippocampal neurons that discriminated between tastes based on palatability. Cells with stronger taste responses typically had weaker spatial responses and taste responses were confined to place cells' firing fields. Hippocampal taste responses emerged later than in other parts of the taste system, suggesting that the hippocampus does not influence taste decisions, but rather associates the hedonic value of tastes consumed within a particular context. This could be one way that animals use past experience to locate food sources.

Prestimulus frontal-parietal coherence predicts auditory detection performance in rats.

Electrophysiology in primates has implicated long-range neural coherence as a potential mechanism for enhancing sensory detection. To test whether local synchronization and long-range neural coherence support detection performance in rats, we recorded local field potentials (LFPs) in frontal and parietal cortex while rats performed an auditory detection task. We observed significantly elevated power at multiple low frequencies (<15 Hz) preceding the target beep when the animal failed to respond to the signal (misses), in both frontal and parietal cortex. In terms of long-range coherence, we observed significantly more frontal-parietal coherence in the beta band (15-30 Hz) before the signal on misses compared with hits. This effect persisted after regressing away linear trends in the coherence values during a session, showing that the excess frontal-parietal beta coherence prior to misses cannot be explained by slow motivational changes during a session. In addition, a trend toward higher low-frequency (<15 Hz) coherence prior to miss trials compared with hits became highly significant when we rereferenced the LFPs to the mean voltage on each recording array, suggesting that the results are specific to our frontal and parietal areas. These results do not support a role for long-range frontal-parietal coherence or local synchronization in facilitating the detection of external stimuli. Rather, they extend to long-range frontal-parietal coherence previous findings that correlate local synchronization of low-frequency (<15 Hz) oscillations with inattention to external stimuli and synchronization of beta rhythms (15-30 Hz) with voluntary or involuntary prolongation of the current cognitive or motor state.