Synaptic Pruning in Schizophrenia: Does Minocycline Modulate Psychosocial Brain Development?

Abstract

Recent studies suggest that the tetracycline antibiotic minocycline, or its cousins, hold therapeutic potential for affective and psychotic disorders. This is proposed on the basis of a direct effect on microglia‐mediated frontocortical synaptic pruning (FSP) during adolescence, perhaps in genetically susceptible individuals harboring risk alleles in the complement component cascade that is involved in this normal process of CNS circuit refinement. In reviewing this field, it is argued that minocycline is actually probing and modulating a deeply evolved and intricate system wherein psychosocial stimuli sculpt the circuitry of the “social brain” underlying adult behavior and personality. Furthermore, this system can generate psychiatric morbidity that is not dependent on genetic variation. This view has important ramifications for understanding “pathologies” of human social behavior and cognition as well as providing long‐sought potential mechanistic links between social experience and susceptibility to mental and physical disease.

Is It Time for a Paradigm Shift in the Treatment of Schizophrenia? The Use of Inflammation-Reducing and Neuroprotective Drugs—A Review

“…The hippocampus, a formation involved in schizophrenia, is one of the targets of minocycline, which stimulates neurogenesis and reduces microglia activation [ 103 ]. Exciting speculation hypothesizes that minocycline acts on microglia and regulates the remodeling synapses and circuits involved in the “social brain” [ 104 ]. Several pieces of evidence have shown that the NMDA glutamate receptor plays a key role in the pathogenesis of schizophrenia [ 105 ]; in fact, molecules that antagonize the NMDA receptor cause the onset of psychotic symptoms.…”

Synaptic pruning during adolescence shapes adult social behavior in both males and females

“…There may also be a role for microglia‐mediated synaptic pruning in the hippocampus during the juvenile period for social development, but the evidence was collected with a global transgenic mouse with microglial deficiencies, and thus, it is difficult to make conclusive statements (Zhan et al., 2014). Finally, although these reports serve as evidence that microglial pruning is important for natural social development, there are also reports suggesting that neurodevelopmental disorders that present with social behavior deficits also have significant dysregulation in microglial pruning, these include, but are not limited to, autism‐spectrum disorder (Arcuri et al., 2017; Kim et al., 2017; Ma et al., 2020; Zhan et al., 2014) and schizophrenia (Boksa, 2012; Howes & McCutcheon, 2017; Jones et al., 2020; Presumey et al., 2017). Critically, dysregulated synaptic pruning during adolescence plays a role in the development of psychotic disorders (Germann et al., 2021).…”

Doxycycline exposure during adolescence and future risk of non-affective psychosis and bipolar disorder: a total population cohort study

“…It is therefore expected that patients with acne (not recorded in the current dataset) might not have been excluded from this sensitivity analysis. Also, to control for acne in the primary analysis would—in contrast to the chosen sensitivity analysis—not avoid potential confounding by more complex causal patterns related to acne, such as suggested by Jones et al [ 28 ]. The result from the separate isotretinoin analysis, that did not indicate any substantial association between the nonantibiotic acne drug and SMI (the crude HR for non-affective psychosis was weakly significant observed in isolation, but did not provide evidence for an association given the total number of sensitivity analysis estimates), was a finding consistent with the null result for isotretinoin reported by Sellgren et al [ 24 ].…”

“…A concern has recently been raised that results from the above studies may be confounded by acne, a condition sometimes treated with long-term prescriptions of minocycline and/or doxycycline [ 28 ].…”