Seizures are bursts of excessive synchronized neuronal activity, suggesting that mechanisms controlling brain excitability are compromised. The voltage-gated potassium channel Kv4.2, a major mediator of hyperpolarizing A-type currents in the brain, is a crucial regulator of neuronal excitability. Kv4.2 expression levels are reduced following seizures and in epilepsy, but the underlying mechanisms remain unclear. Here, we report that Kv4.2 mRNA is recruited to the RNA-induced silencing complex shortly after status epilepticus in mice and after kainic acid treatment of hippocampal neurons, coincident with reduction of Kv4.2 protein. We show that the microRNA miR-324-5p inhibits Kv4.2 protein expression and that antagonizing miR-324-5p is neuroprotective and seizure-suppressive. MiR-324-5p inhibition also blocks kainic acid-induced reduction of Kv4.2 protein in vitro and in vivo and delays kainic acid-induced seizure onset in wild type but not in Kcnd2 knockout mice. These results reveal an important role for miR-324-5p-mediated silencing of Kv4.2 in seizure onset.

Since the discovery of the first microRNA 25 years ago, microRNAs (miRNAs) have emerged as critical regulators of gene expression within the mammalian brain. miRNAs are small non-coding RNAs that direct the RNA induced silencing complex to complementary sites on mRNA targets, leading to translational repression and/or mRNA degradation. Within the brain, intra- and extracellular signaling events tune the levels and activities of miRNAs to suit the needs of individual neurons under changing cellular contexts. Conversely, miRNAs shape neuronal communication by regulating the synthesis of proteins that mediate synaptic transmission and other forms of neuronal signaling. Several miRNAs have been shown to be critical for brain function regulating, for example, enduring forms of synaptic plasticity and dendritic morphology. Deficits in miRNA biogenesis have been linked to neurological deficits in humans, and widespread changes in miRNA levels occur in epilepsy, traumatic brain injury, and in response to less dramatic brain insults in rodent models. Manipulation of certain miRNAs can also alter the representation and progression of some of these disorders in rodent models. Recently, microdeletions encompassing MIR137HG, the host gene which encodes the miRNA miR-137, have been linked to autism and intellectual disability, and genome wide association studies have linked this locus to schizophrenia. Recent studies have demonstrated that miR-137 regulates several forms of synaptic plasticity as well as signaling cascades thought to be aberrant in schizophrenia. Together, these studies suggest a mechanism by which miRNA dysregulation might contribute to psychiatric disease and highlight the power of miRNAs to influence the human brain by sculpting communication between neurons.

In middle-aged female rats, focal ischemia leads to a larger cortical infarction as compared with younger females. To determine if stroke-induced cytotoxicity in middle-aged females was associated with impaired astrocyte function, astrocytes were harvested and cultured from the ischemic cortex of young and middle-aged female rats. Middle-aged astrocytes cleared significantly less glutamate from media as compared with young female astrocytes. Furthermore, astrocyte-conditioned media from middle-aged female astrocytes induced greater migration of peripheral blood monocyte cells (PBMCs) and expressed higher levels of the chemoattractant macrophage inflammatory protein-1 (MIP-1). Middle-aged astrocytes also induced greater migration of neural progenitor cells (NPCs), however, their ability to promote neuronal differentiation of neural progenitor cells was similar to young astrocytes. In males, where cortical infarct volume is similar in young and middle-aged animals, no age-related impairment was observed in astrocyte function. These studies show that the aging astrocyte may directly contribute to infarct severity by inefficient glutamate clearance and enhanced cytokine production and suggest a cellular target for improved stroke therapy among older females.

Summary Genomic studies have repeatedly associated variants in the gene encoding microRNA miR-137 with increased schizophrenia risk. Bioinformatic predictions suggest that miR-137 regulates schizophrenia-associated signaling pathways critical to neural development, but these predictions remain largely unvalidated. In the present study, we demonstrate that miR-137 regulates neuronal levels of p55γ, PTEN, Akt2, GSK3β, mTOR, and rictor. All are key proteins within the PI3K-Akt-mTOR pathway and act downstream of neuregulin (Nrg)/ErbB and BDNF signaling. Inhibition of miR-137 ablates Nrg1α-induced increases in dendritic protein synthesis, phosphorylated S6, AMPA receptor subunits, and outgrowth. Inhibition of miR-137 also blocks mTORC1-dependent responses to BDNF, including increased mRNA translation and dendritic outgrowth, while leaving mTORC1-independent S6 phosphorylation intact. We conclude that miR-137 regulates neuronal responses to Nrg1α and BDNF through convergent mechanisms, which might contribute to schizophrenia risk by altering neural development.

Mounting evidence implicates microRNAs (miRNAs) in the pathology of schizophrenia. These small noncoding RNAs bind to mRNAs containing complementary sequences and promote their degradation and/or inhibit protein synthesis. A single miRNA may have hundreds of targets, and miRNA targets are overrepresented among schizophrenia-risk genes. Although schizophrenia is a neurodevelopmental disorder, symptoms usually do not appear until adolescence, and most patients do not receive a schizophrenia diagnosis until late adolescence or early adulthood. However, few studies have examined miRNAs during this critical period. First, we examine evidence that the miRNA pathway is dynamic throughout adolescence and adulthood and that miRNAs regulate processes critical to late neurodevelopment that are aberrant in patients with schizophrenia. Next, we examine evidence implicating miRNAs in the conversion to psychosis, including a schizophrenia-associated single nucleotide polymorphism in MIR137HG that is among the strongest known predictors of age of onset in patients with schizophrenia. Finally, we examine how hemizygosity for DGCR8, which encodes an obligate component of the complex that synthesizes miRNA precursors, may contribute to the onset of psychosis in patients with 22q11.2 microdeletions and how animal models of this disorder can help us understand the many roles of miRNAs in the onset of schizophrenia.