Higher brain functions and cognition undergo extensive development during adolescence, when psychiatric disorders such as schizophrenia typically onset. Understanding how developmental processes during adolescence interact with schizophrenia pathophysiology and risk remains a central goal in psychiatry. Here we focus on mismatch negativity, a well-established biomarker of schizophrenia, and show that a key component of mismatch negativity, “deviance detection”, emerges during adolescence in mouse primary visual cortex, along with a refinement of fronto-visual functional connectivity.
In contrast, we found stimulus-specific adaptation—another component of mismatch negativity—to be present prior to adolescence. Because microglia are implicated in schizophrenia risk and disease states, we further investigated what role microglia may play in the development of mismatch responses under physiological conditions. We found that microglial depletion with PLX5622 in adolescence arrests the development of resting oscillations in frontal areas, but does not affect the development of deviance detection, other signatures of visual context processing, or prefrontal–visual functional connectivity.
Our findings suggest (a) a key component of mismatch negativity develops in adolescence, a period of vulnerability to schizophrenia, and (b) the development underlying this component does not require robust microglia activity, clarifying the developmental role of microglia in higher-order visual processing. Schizophrenia pathology follows a neurodevelopmental arc, and symptoms typically onset in late adolescence and early adulthood [1]. An understanding of brain functions that both i) are altered in the disorder and ii) mature during adolescence could provide key pathophysiological insights.
One key function altered in schizophrenia is sensory processing and integration [2, 3]. The electrophysiological marker known as mismatch negativity (MMN) indexes these functions and is reliably deficient in schizophrenia in both visual and auditory domains [4,5,6]. MMN is most often measured during a sensory “oddball” sequence, wherein a series of repeated images is presented and occasionally interrupted by a different, “deviant” image; the difference in responses to repeated versus deviant stimuli constitutes MMN [7,8,9].
Thus, MMN reflects how sensory cortex processes inputs in context and is thereby considered an index of integrative, sensory-cognitive function [10]. Consistent with this interpretation, MMN involves both sensory and frontal cortices, drivers of feedforward and feedback activity, respectively [11, 12]. While MMN deficits are well-established in schizophrenia, and MMN function relies on regions that develop in adolescence (i.e., frontal cortex [13]), whether MMN develops during adolescence remains unclear [14,15,16].
One factor contributing to this lack of clarity arises from the way in which MMN is commonly computed. Typically, researchers subtract EEG responses to deviant (“oddball”) from responses to redundant (“standard”) stimuli, which standardizes the measure but conflates two processes: stimulus-specific adaptation (reduced responses to repetition) and genuine deviance detection (enhanced responses to unexpected events) [17]. Stimulus-specific adaptation is present even in precortical processing stages, whereas deviance detection arises in primary sensory cortex and requires both feedback from higher areas and cortical interneuron populations [7, 18,19,20,21].
Extract — continue reading at the source.
