Recent studies combining pharmacological, behavioral, electrophysiological and molecular approaches indicate that depression results from maladaptive neuroplastic processes occurring in defined frontolimbic circuits responsible for emotional processing such as the prefrontal cortex, hippocampus, amygdala and ventral striatum. However, the exact mechanisms controlling synaptic plasticity that are disrupted to trigger depressive conditions have not been elucidated. Since glial cells (astrocytes and microglia) tightly and dynamically interact with synapses, engaging a bi-directional communication critical for the processing of synaptic information, we now revisit the role of glial cells in the etiology of depression focusing on a dysfunction of the “quad-partite” synapse. This interest is supported by the observations that depressive-like conditions are associated with a decreased density and hypofunction of astrocytes and with an increased microglia “activation” in frontolimbic regions, which is expected to contribute for the synaptic dysfunction present in depression. Furthermore, the traditional culprits of depression (glucocorticoids, biogenic amines, brain-derived neurotrophic factor, BDNF) affect glia functioning, whereas antidepressant treatments (serotonin-selective reuptake inhibitors, SSRIs, electroshocks, deep brain stimulation) recover glia functioning. In this context of a quad-partite synapse, systems modulating glia-synapse bidirectional communication—such as the purinergic neuromodulation system operated by adenosine 5′-triphosphate (ATP) and adenosine—emerge as promising candidates to “re-normalize” synaptic function by combining direct synaptic effects with an ability to also control astrocyte and microglia function. This proposed triple action of purines to control aberrant synaptic function illustrates the rationale to consider the interference with glia dysfunction as a mechanism of action driving the design of future pharmacological tools to manage depression.

Epidemiologic studies have provided compelling evidence that prenatal stress, through excessive maternal glucocorticoids exposure, is associated with psychiatric disorders later in life. We have recently reported that anxiety associated with prenatal exposure to dexamethasone (DEX, a synthetic glucocorticoid) correlates with a gender‐specific remodeling of microglia in the medial prefrontal cortex (mPFC), a core brain region in anxiety‐related disorders. Gender differences in microglia morphology, the higher prevalence of anxiety in women and the negative impact of anxiety in cognition, led us to specifically evaluate cognitive behavior and associated circuits (namely mPFC‐dorsal hippocampus, dHIP), as well as microglia morphology in female rats prenatally exposed to dexamethasone (in utero DEX, iuDEX). We report that iuDEX impaired recognition memory and deteriorated neuronal synchronization between mPFC and dHIP. These functional deficits are paralleled by microglia hyper‐ramification in the dHIP and decreased ramification in the mPFC, showing a heterogeneous remodeling of microglia morphology, both postnatally and at adulthood in different brain regions, that differently affect mood and cognition. The chronic blockade of adenosine A2A receptors (A2AR), which are core regulators of microglia morphology and physiology, ameliorated the cognitive deficits, but not the anxiety‐like behavior. Notably, A2AR blockade rectified both microglia morphology in the dHIP and the lack of mPFC‐dHIP synchronization, further heralding their role in cognitive function.

KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 participates in functions unrelated to neuronal migration. Supporting this hypothesis, overexpression of KIAA0319 repressed axon growth in hippocampal and dorsal root ganglia neurons; the intracellular domain of KIAA0319 was sufficient to elicit this effect. A similar inhibitory effect was observed in vivo as axon regeneration was impaired after transduction of sensory neurons with KIAA0319. Conversely, the deletion of Kiaa0319 in neurons increased neurite outgrowth in vitro and improved axon regeneration in vivo. At the mechanistic level, KIAA0319 engaged the JAK2-SH2B1 pathway to activate Smad2, which played a central role in KIAA0319-mediated repression of axon growth. In summary, we establish KIAA0319 as a novel player in axon growth and regeneration with the ability to repress the intrinsic growth potential of axons. This study describes a novel regulatory mechanism operating during peripheral nervous system and central nervous system axon growth, and offers novel targets for the development of effective therapies to promote axon regeneration.

Microglia cells exert a critical role in brain development, mainly supported by their immune functions, which predicts an impact on the genesis of psychiatric disorders. In fact, microglia stress during gestation is, for instance, associated with chronic anxiety and cognitive deficits accompanied by long‐lasting, region‐ and sex‐specific changes in microglia morphology. We recently reported that the pattern of microglia morphologic plasticity, which is sex‐determined, impacts on anxious‐like behaviour and cognition. We also reported that the pharmacologic blockade of adenosine A2A receptors (A2AR) is able to reshape microglia morphology, in a sex‐specific manner and with behavioural sequelae. In order to better understand the role of A2AR in the sex differentiation of microglia, we now compared their morphology in wild‐type and A2AR knockout male and female C57BL/6 mice in two cardinal brain regions implicated in anxiety‐like behaviour and cognition, the prefrontal cortex (PFC) and the dorsal hippocampus (dHIP). We report interregional differences between PFC and dHIP in a sex‐specific manner: while males presented more complex microglia in the dHIP, microglia from females had a more complex morphology in the PFC. Surprisingly, the genetic deletion of A2AR did not alter these sex differences, but promoted the exclusive remodelling (increase in complexity) in PFC microglia from females. These findings further support the existence of a heterogeneous microglial network, distinct between sexes and brain regions, and help characterizing the role of A2AR in the sex‐ and brain region‐specific morphologic differentiation of microglia.

Orally administered antipsychotic drugs are the first-line treatment for psychotic disorders, such as schizophrenia and bipolar disorder. Nevertheless, adverse drug reactions jeopardize clinical outcomes, resulting in patient non-compliance. The design formulation strategies for enhancing brain drug delivery has been a major challenge, mainly due to the restrictive properties of the blood–brain barrier. However, recent pharmacokinetic and pharmacodynamic in vivo assays confirmed the advantage of the intranasal route when compared to oral and intravenous administration, as it allows direct nose-to-brain drug transport via neuronal pathways, reducing systemic side effects and maximizing therapeutic outcomes. In addition, the incorporation of antipsychotic drugs into nanosystems such as polymeric nanoparticles, polymeric mixed micelles, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, nanoemulgels, nanosuspensions, niosomes and spanlastics, has proven to be quite promising. The developed nanosystems, having a small and homogeneous particle size (ideal for nose-to-brain delivery), high encapsulation efficiency and good stability, resulted in improved brain bioavailability and therapeutic-like effects in animal models. Hence, although it is essential to continue research in this field, the intranasal delivery of nanosystems for the treatment of schizophrenia, bipolar disorder and other related disorders has proven to be quite promising, opening a path for future therapies with higher efficacy.