Dissecting the cellular mechanisms of NMDA receptor antagonist-induced disruptions to working memory and gamma oscillations
AuthorSokolenko, Elysia Maree
Document TypePhD thesis
Access StatusOpen Access
© 2019 Elysia Maree Sokolenko
Schizophrenia is a chronic, heterogeneous psychiatric disorder characterised by the experience of a suite of positive, negative and cognitive symptoms. Neural oscillations in the gamma frequency range (30-80 Hz) are associated with some of the same cognitive process disrupted in schizophrenia. Gamma oscillations arise from a circuit between inhibitory parvalbumin-positive (PV+) interneurons and excitatory pyramidal cells. PV+ interneurons and gamma oscillations are both altered in schizophrenia, inviting the hypothesis that PV+ interneuron dysfunction drives gamma deficits and that this underlies cognitive impairment in schizophrenia. Schizophrenia-like behavioural impairments and gamma disruptions can both be modelled in rodents by administering NMDA receptor (NMDAr) antagonists, such as MK-801 and ketamine. NMDAr hypofunction rodent models have been widely used to explore the functional relevance of PV+ interneuron dysfunction and gamma oscillatory disruptions to cognitive impairment. The first aim of this thesis was to further examine whether gamma oscillatory disruptions are mechanistically linked to cognitive impairment. Second, this thesis examined whether NMDAr antagonists act at the cell types that generate gamma activity to disrupt gamma and cognition. I first assessed whether gamma and working memory impairments induced by MK-801 could both be recovered with an agonist of the metabotropic glutamate receptor type 2/3 receptor (mGluR2/3), LY379268. MK-801 impaired performance on the trial-unique nonmatching-to-location (TUNL) test of working memory in the rodent operant touchscreen system and decreased auditory evoked gamma power. It also increased ongoing gamma power and regional gamma coherence. Pre-treatment with LY379268 recovered the MK801-induced increase in ongoing gamma power and regional gamma coherence but failed to improve the reduction in evoked gamma power and working memory. This suggested that aberrant ongoing gamma and regional gamma coherence may not be mechanistically linked to working memory impairment. Next, I examined the contribution of the NMDAr on PV+ interneurons and pyramidal cells to working memory impairment induced by MK-801. Excision of the obligatory subunit of the NMDAr, GluN1, was driven in either PV+ interneurons or forebrain pyramidal cells, expressing calcium/calmodulin-dependent protein kinase II alpha (CaMKIIa). PV GluN1 KO and CaMKIIa GluN1 KO mice performed at the same level as their wildtype (WT) littermates on the TUNL test of working memory. Interestingly, PV GluN1 KO mice were sensitised to the MK-801-induced decrease in accuracy and increase in perseveration on the task. In contrast, the response to MK-801 was no different in the CaMKIIa GluN1 KO mice compared to WTs. This suggests that NMDAr hypofunction at PV+ interneurons or pyramidal cells is not sufficient to impair working memory. Further, while the NMDAr on neither cell type exclusively mediates the effects of MK-801 on working memory, NMDAr hypofunction on PV+ interneurons may sensitise circuits for NMDAr hypofunction at other cell types to impair working memory. Lastly, I examined whether ablation of PV+ interneurons in the medial prefrontal cortex (mPFC) could disrupt gamma activity and if this manipulation would affect the MK-801-induced deficits in gamma. To achieve this, diphtheria toxin (DT) was infused into the mPFC of mice expressing the diphtheria toxin receptor (DTR) exclusively in PV+ interneurons, expected to drive loss of that cell only in the infused region. Infusion of DT did not alter ongoing gamma, evoked gamma or regional gamma coherence. It did, however, blunt the MK-801-induced increase in ongoing gamma power, while the decrease in evoked power and increase in regional coherence were unaffected. This suggests that PV+ interneurons may play a redundant role in maintaining gamma activity under normal conditions, but this cell type contributes to the increase in ongoing gamma power induced by NMDAr hypofunction. To summarise, my thesis shows that the effects of NMDAr antagonists on ongoing gamma, evoked gamma and regional gamma coherence are likely mediated by different mechanisms. Further, the different gamma disruptions may be functionally relevant to specific behavioural impairments arising from NMDAr hypofunction. More specifically, NMDAr hypofunction at PV+ interneurons can be linked to increased ongoing gamma power but may not contribute to the decrease in evoked gamma power. Further, elevated ongoing gamma power might not be mechanistically linked to working memory impairment. Lastly, NMDAr hypofunction at PV+ interneurons may not be sufficient to impair working memory, but it could exacerbate the effects of NMDAr hypofunction at other cell types on this process. In all, a complex relationship appears to exist between NMDAr hypofunction, PV+ interneuron dysfunction, gamma deficits and cognitive impairment. This guides future studies in identifying biomarkers and potential treatment targets for the cognitive symptoms of schizophrenia.
KeywordsSchizophrenia; Working memory; Gamma oscillations; NMDA receptors; Parvalbumin-positive interneurons
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