The immediate-early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Arc protein is localized to excitatory synapses, where it controls AMPA receptor endocytosis, and to the nucleus, where it associates with Tip60, a subunit of a chromatin modifying complex. Here we show that Arc interacts with dynamic chromatin loops and associates with histone markers for active enhancers and transcription in cultured hippocampal neurons. When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes. Many gene families were affected by the absence of Arc, most notably those associated with synaptic function, neuronal plasticity, intrinsic excitability (channels, receptors, transporters), and signaling pathways (transcription factors/regulators). Interestingly, about 100 genes whose activitydependent expression level depends on Arc are associated with the pathophysiology of Alzheimer's disease, suggesting a critical role for Arc in the development of neurodegenerative disorders. When endogenous Arc expression was induced in a non-neuronal cell line (HEK293T), the transcription of many neuronal genes was increased, suggesting Arc can control expression in the absence of activated signaling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and a significant factor underlying the pathophysiology Alzheimer's disease.

The immediate early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Here, we show that Arc interacts with dynamic chromatin and closely associates with histone markers for active enhancers and transcription in cultured rat hippocampal neurons. Both these histone modifications, H3K27Ac and H3K9Ac, have recently been shown to be upregulated in late-onset Alzheimer’s disease (AD). When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes, which included genes associated with synaptic function, neuronal plasticity, intrinsic excitability, and signalling pathways. Interestingly, about 100 Arc-dependent genes are associated with the pathophysiology of AD. When endogenous Arc expression was induced in HEK293T cells, the transcription of many neuronal genes was increased, suggesting that Arc can control expression in the absence of activated signalling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and suggest that it plays a significant role in the pathophysiology of AD.

Background: Tissue plasminogen activator (tPA) modulates many physiological and pathological processes. Results: tPA cleaves the NR2B subunit of the NMDA receptor. Conclusion: Deletion of amino acid residues at the amino-terminal domain can alter pharmacological properties of NMDA receptors. Significance: Identifying novel substrates for tPA may be crucial for stroke therapy and the design of therapeutic molecules targeted at the ATD of the NR2B subunit.

Bacopa monnieri is a plant used as a nootropic in Ayurveda, a 5000-year-old system of traditional Indian medicine. Although both animal and clinical studies supported its role as a memory enhancer, the molecular and cellular mechanism underlying Bacopa’s nootropic action are not understood. In this study, we used deep sequencing (RNA-Seq) to identify the transcriptome changes upon Bacopa treatment on SH-SY5Y human neuroblastoma cells. We identified several genes whose expression levels were regulated by Bacopa. Biostatistical analysis of the RNA-Seq data identified biological pathways and molecular functions that were regulated by Bacopa, including regulation of mRNA translation and transmembrane transport, responses to oxidative stress and protein misfolding. Pathway analysis using the Ingenuity platform suggested that Bacopa may protect against brain damage and improve brain development. These newly identified molecular and cellular determinants may contribute to the nootropic action of Bacopa and open up a new direction of investigation into its mechanism of action.