Microglia induce auditory dysfunction after status epilepticus in mice.

Auditory dysfunction and increased neuronal activity in the auditory pathways have been reported in patients with temporal lobe epilepsy, but the cellular mechanisms involved are unknown. Here, we report that microglia play a role in the disinhibition of auditory pathways after status epilepticus in mice. We found that neuronal activity in the auditory pathways, including the primary auditory cortex and the medial geniculate body (MGB), was increased and auditory discrimination was impaired after status epilepticus. We further demonstrated that microglia reduced inhibitory synapses on MGB relay neurons over an 8-week period after status epilepticus, resulting in auditory pathway hyperactivity. In addition, we found that local removal of microglia from the MGB attenuated the increase in c-Fos+ relay neurons and improved auditory discrimination. These findings reveal that thalamic microglia are involved in auditory dysfunction in epilepsy.

Identification of an exporter that regulates vitamin C supply from blood to the brain.

Vitamin C (VC) distribution in our body requires VC transporters. However, mammalian VC exporters are yet to be identified. Herein, to unravel this long-standing mystery, we focused on the pathways whereby VC moves from blood to the brain, which should require a VC entrance and exit system composed of an importer and a latent exporter. Via cell-based transport analyses of VC efflux and using knockout mice generated via the CRISPR-Cas9 system, we identified GLUT12/SLC2A12 as a physiologically important VC efflux protein expressed in the choroid plexus; Glut12/Slc2a12 knockout halved the cerebral VC levels, markedly increased VC accumulation in the choroid plexus, and reduced the cerebrospinal fluid VC levels. These findings facilitate our understanding of VC regulation and the physiological impact of VC in our body.

Astrocytic cAMP modulates memory via synaptic plasticity.

Astrocytes play a key role in brain homeostasis and functions such as memory. Specifically, astrocytes express multiple receptors that transduce signals via the second messenger cAMP. However, the involvement of astrocytic cAMP in animal behavior and the underlying glial-neuronal interactions remains largely unknown. Here, we show that an increase in astrocytic cAMP is sufficient to induce synaptic plasticity and modulate memory. We developed a method to increase astrocytic cAMP levels in vivo using photoactivated adenylyl cyclase and found that increased cAMP in hippocampal astrocytes at different time points facilitated memory formation but interrupted memory retention via NMDA receptor-dependent plasticity. Furthermore, we found that the cAMP-induced modulation of memory was mediated by the astrocyte-neuron lactate shuttle. Thus, our study unveils a role of astrocytic cAMP in brain function by providing a tool to modulate astrocytic cAMP in vivo.

Microglia after Seizures and in Epilepsy.

Microglia are the resident immune cells in the brain that constitute the brain's innate immune system. Recent studies have revealed various functions of microglia in the development and maintenance of the central nervous system (CNS) in both health and disease. However, the role of microglia in epilepsy remains largely undiscovered, partly because of the complex phenotypes of activated microglia. Activated microglia likely exert different effects on brain function depending on the phase of epileptogenesis. In this review, we mainly focus on the animal models of temporal lobe epilepsy (TLE) and discuss the proepileptic and antiepileptic roles of activated microglia in the epileptic brain. Specifically, we focus on the roles of microglia in the production of inflammatory cytokines, regulation of neurogenesis, and surveillance of the surrounding environment in epilepsy.

Differentiation of Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons in Mouse Hippocampal Slice Cultures.

Potential clinical applications of neurons derived from human induced pluripotent stem cells (hiPSC-neurons) for drug screening and transplantation therapies have received considerable attention. However, it remains unclear whether and how transplanted hiPSC-neurons are incorporated into pre-existing neural circuits. Here we developed a co-culture system of hiPSC-neurons and mouse hippocampal slices to examine the differentiation of hiPSC-neurons in pre-existing neural circuits. hiPSC-neurons transplanted in mouse hippocampal slices expressed the hippocampal neuron-specific markers HuB and Prox1 after 7 days of culture, while those markers were scarcely expressed in hiPSC-neurons cultured on glass dishes. Furthermore, hiPSC-neurons transplanted in the dentate gyrus (DG) of slice cultures grew to exhibit dentate granule cell-like morphologies, including besom-shaped dendrites. Similarly, hiPSC-neurons transplanted in the CA1 region of slice cultures grew to exhibit CA1 pyramidal cell-like morphologies, including primary apical and multiple basal dendrites with synaptic spines. Additionally, these cells projected axons toward the entorhinal cortex (EC) as observed in vivo. These data suggest that hiPSC-neurons were anatomically integrated into pre-existing neural circuits in a region-specific manner. Thus, the co-culture system will be useful for the study of efficient strategies to differentiate transplanted hiPSC-neurons.