Here, we studied working memory function in healthy controls, patients with schizophrenia, and patients recovering from anti-NMDAR encephalitis (see “Methods“ section and Supplementary Table 1). Yet, the specific neural alterations by which NMDAR hypofunction could lead to memory deficits in schizophrenia are still under debate 7, 8.
Indeed, reduced prefrontal NMDAR density characterizes this disease 9. In addition, hypofunction of NMDARs is linked to psychiatric disease, in particular schizophrenia 6, and it possibly contributes to abnormal working memory function in patients with schizophrenia 7, 8. The NMDA receptor (NMDAR) subserves memory mechanisms at several timescales, including sustained working memory delay activity 1, 2 and different temporal components of synaptic potentiation 3, 4, 5. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. We then simulated this finding with NMDAR-dependent synaptic alterations in a microcircuit model of prefrontal cortex. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We first quantified shared working memory alterations in a delayed-response task.
We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders.
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