Microglial Activation and the Onset of Psychosis.

Microglial activationmay represent a proximalmechanismby which both immunologic and neuroplasticity-related etiological factors influence thepathophysiologyof schizophrenia. Microglia are essentially immune cells operating in the brain; their activation isakeyconstituentofneuroinflammation.This role potentially links microglial activation with evidence of inherited structural genetic variations in and altered expression of genes that control immunologic/inflammatory signaling in schizophrenia (1). In addition, activated microglia eliminate inactive or weak synapses, a process that depends critically on long-term potentiation and other aspects of synaptic plasticity (2). This role potentially links microglial activation with evidence of inherited structural variations in and altered expression of genes involved in N-methyl-daspartate (NMDA)-dependent plasticity in schizophrenia (3). Whether due to disturbances in immunologic and/or plasticity-related signaling, over-active microglia may contribute to the pathophysiology of this disorder by decreasing spine and synapse density on glutamatergic cortical pyramidal neurons (4) below a threshold critical for integrated functioning of networks relevant to reality testing (5). Some, though not all, positron emission tomography (PET) studies of the 18kD translocator protein (TSPO),which is expressed in microglia, have reported increasedmicroglial activation in patients with schizophrenia compared with healthy control subjects (6). However, studies of patients with established illness cannot differentiate which neural changes are causal, which are epiphenomena, and which are secondary to factors associated with chronicity of illness or antipsychotic drug treatment. Teasing these alternatives apart requires prospective evaluation prior to the onset of illness and initiation of treatment. It is thus provocative that in this issue of the Journal, Bloomfield et al. (6) report on the results of a PET study with [C]PBR28 comparing microglial activation in a sample of individuals at ultra high risk for psychosis compared with demographically similar healthy control subjects. The binding ratio in prefrontal and temporal gray matter (relative to whole brain) was elevated in the ultra-high-risk subjects, with a positive correlation between binding ratio and prodromal symptom severity. This study is the first using a central measure of microglial activation to find evidence supporting the theory that a neuroinflammatory process may be involved in the development of psychosis. That this effect was independent of antipsychotic drug exposure in the ultra-high-risk cases (who had none) and that even larger elevations were observed in a parallel case-control study among patients with established schizophrenia are also encouraging to this view. Because of the relative quantitation method used in this study (whereby binding potential in cortical gray matter areas was expressed as a ratio of binding potential in the brain overall), it remains ambiguous whether the higher binding ratios in ultra-high-risk cases are due to higher TSPO expression in cortex, lower TSPO expression elsewhere (e.g., white matter, subcortical nuclei), or both. When quantified using more traditional methods (volume of distribution or VT), the groups did not differ in TSPO expression in gray matter or elsewhere (6). Clearly, additional (and larger) studies of ultra-high-risk cases are needed to resolve this question. Another limitation of the study is the lack of information on outcome among the ultra-high-risk cases; thus, we do not yet know if microglial activation specifically precedes and predicts onset of psychosis or is characteristic of at-risk mental states in general. That [C]PBR28 binding correlates with prodromal symptom severity helps in this regard because higher prodromal symptom severity at baseline is highly predictive of conversion to psychosis in this population (7). The search for a psychosis-triggering mechanism profits greatly from a prospective vantage point, as afforded by the prodromal risk paradigm. However, with only a single scan collected at a baseline assessment, it is not clear whether microglial activation increases as cases move from an at-risk vulnerability state to a fully psychotic state, as one would expect if it participates causally in symptom formation. Longitudinal evaluation of ultra-high-risk cases can help to differentiate the likely role of a given process in pathophysiology. A marker that is stably deviant in those who develop psychosis from preto postonset may be necessary, but clearly is not sufficient for psychotic symptom formation. Conversely, amarker thatworsensas symptomsworsen in the ramp-up to full psychosis has the potential to represent a proximal sufficient cause of psychosis (5). If a disruption in brain connectivity, driven primarily by a reduction in dendritic spines expressing NMDA synapses A question of major importance is whether increasing neuroinflammation precedes and predicts changes in cortical gray matter and functional connectivity prior to onset.