Neurogranin regulates sensorimotor gating through cortico-striatal circuitry

Abstract

Glutamate dysregulation is known to contribute to many psychiatric disorders including schizophrenia. Aberrant cortico-striatal activity and therefore glutamate levels might be relevant to this disease characterized by reduced prepulse inhibition (PPI), however, the molecular and behavioral mechanism of the pathophysiology of schizophrenia remains unclear. The focus of this study was to contribute to the current understanding of the glutamate and neurogranin (Ng) pathway, in relation to the cortico-striatal pathology of schizophrenia using a mouse model. A variant of the Ng gene has been detected in people with schizophrenia, implicating maladaptation of cortical glutamate signaling and sensorimotor gating. To test Ng-mediated PPI regulation in the mouse model, we utilized Ng null mice, viral-mediated Ng expression, and genetics approaches. Our results demonstrate that lack of Ng in mice decreases PPI. Ng over-expression in the prefrontal cortex (PFC) increases PPI, while Ng expression in either the nucleus accumbens (NAc) or hippocampus induces no change in PPI. Using optogenetics and chemogenetics, we identified that cortico-striatal activation is involved in PPI regulation. Finally, pharmacological regulation of Ng using glutamate receptor inhibitors demonstrated altered PPI between genotypes. In this study, we have investigated the impact of Ng expression on sensorimotor gating. This study contributes to a better understanding of the glutamatergic theory of schizophrenia, opening novel therapeutic avenues that may lead to glutamatergic treatments to ameliorate the symptoms of schizophrenia.

Decreased nesting behavior, selective increases in locomotor activity in a novel environment, and paradoxically increased open arm exploration in Neurogranin knockout mice

“…We also reproduced behavioral phenotypes in the mutant mice that have been reported (available as supplementary materials). The Nrgn KO mice exhibited decreased prepulse inhibition 18 (Figure S5; prepulse inhibition [%]; P = 0.0315), decreased immobility 15 in the Porsolt forced swim test (Figure S5; immobility [%] on day 2; P = 0.067), and a tendency of decreased sociability and social preference in male mice 15 (Figure S4, F, and G; time spent around a stranger cage [ratio]; P = 0.2069 and P = 0.3295, respectively). Female mutant mice showed a significantly decreased ratio of time spent around stranger cage both in sociability and social preference tests, while sexual attraction of the male stranger mice might have confounded their social behaviors (Figure S4, H and I; time spent around a stranger cage [ratio]; P = 0.0054 and P = 0.0145, respectively).…”

“…These findings imply that NRGN might be involved in the pathophysiology and pathogenesis of various neuropsychiatric disorders. Since the generation of Nrgn knockout ( Nrgn KO) mice, 1 several behavioral studies have been carried out on these mice, and hyperactivity, 15 deficits in spatial learning, 16,17 impaired sociability, 15 and decreased prepulse inhibition 18 were identified, suggesting that these mice recapitulate some symptoms of neuropsychiatric disorders. To further validate Nrgn KO mice as a model of certain neuropsychiatric diseases, we assessed various behavioral domains in aged Nrgn KO mice using a comprehensive behavioral test battery 19–21 (summary of the results and ages of the mice are available in the supplementary table).…”

“…We also reproduced most of the behavioral phenotypes that were previously reported. Until recently, Nrgn KO mice have been suggested to be an animal model of schizophrenia and Jacobsen's syndrome with ADHD symptoms, 15 as these mice show hyperactivity, 15 altered anxiety‐like behavior, 16 decreased sociability, 15 impaired reference memory, 15–17 and impaired sensorimotor gating 18 . Behavioral phenotypes of commonly used AD model mice such as decreased nesting behavior, 31,35–37 hyperactivity, 31,37–41 impaired sociability, 35 impaired working/reference memory, 31,35,38,39,42–45 and abnormal sensorimotor gating 46,47 overlap with those of Nrgn KO mice, which suggests the potential of Nrgn KO as a model of AD.…”

Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior

“…4f ), confirming that the observed enrichment of high glycine content proteins in the fraction of downregulated proteins in the Nsun2 mutant cortex do not reflect a non-specific decline of the neuronal proteome overall. Notably, a subset of 50 downregulated proteins known to be involved in excitatory synaptic transmission (Supplementary Table 3 ), including Neurogranin (Nrgn) as a key regulator of glutamate NMDA receptor-dependent intracellular signaling in PFC 37 , 38 , and calcium voltage-gated channel auxiliary subunit gamma 8 (Cacng8), regulating AMPA receptor intramembranous distribution 39 , displayed even higher average glycine content (7.62%; Supplementary Fig. 4f ).…”

Regulation of Pv‐specific interneurons in the medial prefrontal cortex and reward‐seeking behaviors

“…Cre‐dependent DREADD constructs (AAV‐hSyn‐DIO‐mCherry (RRID:Addgene_50459); AAV‐hSyn‐DIO‐hM3D(Gq)‐mCherry (RRID:Addgene_44361); and AAV‐hSyn‐HA‐hM3D(Gq)‐IRES‐mCitrine (RRID:Addgene_50463)) were purchased from Addgene. For DREADD expression in the target brain regions, stereotaxic injections of AAV viruses were conducted as described previously (Sullivan et al., 2019). 9‐weeks old Pv‐Cre mice were anesthetized with 2%–3% isoflurane gas and placed in a digital stereotaxic alignment system (Model 1900; David Kopf Instruments).…”