A groundbreaking study reveals a potential link between high calcium levels in brain microglia and anxiety, offering new avenues for treating neuropsychiatric disorders.
High calcium levels in a specialised group of immune cells in the brain called microglia could be linked to anxiety, according to a study, results from which may pave way for new treatments for neuropsychiatric disorders.
Previous studies had found that microglia can act as accelerators and brakes for anxiety in mice.
Researchers from the University of Utah have identified calcium as a key chemical signal that triggers microglia during obsessive-compulsive and anxiety-related behaviours in healthy mice, and in a mouse model of obsessive compulsive spectrum disorder (OCSD) and chronic anxiety.
The discovery, published in a paper in the journal Molecular Psychiatry, establishes a new framework to study how anxiety arises and persists through calcium signals in microglia.
"Microglia are not just passive immune cells but actively control anxiety-, grooming-, and obsessive-compulsive-related behaviours through specific molecular signals like calcium," first author Naveen Nagarajan, assistant professor of paediatrics at the Pediatric Research Institute at the University of Louisville, said.
"This makes microglia a key target to understand and treat neuropsychiatric disorders," Nagarajan said.
The researchers used genetic tools combined with light-based cell stimulation to temporarily activate a group of microglia called the 'Hoxb8' in healthy mice, who were seen to perform grooming and anxiety-like behaviours.
However, it was not known what event within the Hoxb8 microglia cells could be triggering the behaviours.
The team found that calcium signalling within microglia is pivotal -- high levels of calcium act as a critical molecular signal that triggers obsessive grooming and anxiety.
They explained that calcium ions enable microglia cells to encode and transmit instructions that shape behavioural output.
Normal mice performing grooming, freezing in place, or other anxiety-like behaviours was related with spiked calcium levels in the Hoxb8 microglia and when the behaviours stopped, calcium was seen to return to normal levels.
Further, calcium was found to be always high in Hoxb8 mutant microglia among mice with chronic anxiety and OCSD.
The authors "show that the molecular signals for inducing anxiety and/or grooming in response to optogenetic (light-based genetic) activation are calcium ions. Conversely, induction of grooming and anxiety in mice produces calcium transients within microglia."
The research opens the door to a new class of therapies that target the brain's immune cells and precisely modulate calcium signalling pathways -- the approach may hold the potential for more effective, targeted, and durable treatments, the researchers said.