Neuron-microglia interactions during gamma-frequency oscillations

Abstract

Gamma frequency oscillations are formed by the synchronous firing of excitatory and inhibitory interneurons, at a frequency between 25 – 100 Hz. Gamma oscillations are disrupted in a variety of different neurological diseases, including Alzheimer’s disease (AD) and schizophrenia and it is has been proposed that reinstating these dysfunctional oscillations could be used as effective treatments for these conditions. A recent series of studies have revealed that entraining gamma oscillations using sensory stimulation at a frequency of 40 Hz in mouse models of AD can reduce the presence of pathology such as amyloid beta (Aβ) and tau, while also improving the cognitive deficits associated with the disease. These effects are thought to be mediated by microglia, the immune cells of the central nervous system (CNS). Specifically, microglia take on an ‘activated’ phenotype and were shown to contain pathological proteins Aβ and tau.

The neurophysiological mechanisms underlying this neuroimmune interaction are currently unknown. Consequently, pharmacological and optogenetic ex vivo brain slice models of gamma-frequency oscillations were used and microglia morphology was assessed post-hoc using immunofluorescence imaging analysis. In these experiments, I demonstrate that microglia morphology is significantly altered in response to both pharmacological and optogenetic stimulation of gamma-frequency oscillations. Furthermore, I reveal that this neuroimmune interaction is mediated by activation of colony stimulating factor 1 (CSF-1) receptors and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signalling pathway. Additionally, I investigate this gamma oscillation interaction with microglia in the context of neuropsychiatric disease, as aberrant gamma frequency oscillations are reminiscent of neural activity observed in psychotic episodes. Here, I establish that application of atypical antipsychotic medications clozapine and quetiapine can block this gamma oscillation activation of microglia. Moreover, I demonstrate that blockade of microglia activation by atypical antipsychotics is mediated by histamine 1 receptors. Collectively, these findings provide important mechanistic understanding of how gamma-frequency oscillation activate microglia and reveal pathways that could be targeted in both neurodegenerative and neuropsychiatric diseases.