Probing the Genetics of Learning and Memory

December 2, 2016

Pitt Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterized by a characteristic facial appearance, poor muscle tone and coordination, unusual breathing patterns, delayed development, and a profound language impairment. The cause is haploinsufficiency of the gene for transcription factor 4 (Tcf4), a gene that has also been associated with schizophrenia. To better understand how a mutation in Tcf4 could lead to the array of symptoms associated with PTHS, Vanderbilt Basic Sciences investigator David Sweatt and his laboratory created a mouse model [Tcf4(+/-)] that bears a mutation of the Tcf4 gene structurally similar to those observed in human PTHS patients. The researchers verified that many of the developmental and behavioral abnormalities exhibited by Tcf4(+/-) mice were consistent with symptoms of PTHS. They then carried out RNA-seq and genome-wide methylation studies to investigate how the Tcf4(+/-) mutation affects gene expression in the hippocampus of affected mice. The results revealed both up- and down-regulation of key biochemical pathways associated with neuronal plasticity, learning, and memory. Of particular interest was the finding that the gene for histone deacetylase 2 (Hdac2) was markedly upregulated in Tcf4(+/-) mice.  Histone deacetylase 2 removes acetyl groups from the lysine residues of histones, an important step in histone-mediated regulation of gene transcription. Consistent with this observation, the researchers found that treating Tcf4(+/-) mice with a nonselective HDAC inhibitor or with an Hdac2-selective antisense oligonucleotide resulted in a striking improvement in many of the Tcf4(+/-) mutation-related disabilities. The results provide a wealth of new information concerning the genetic and epigenetic regulation of learning and memory while also suggesting an exciting new treatment possibility for PTHS patients. The work is published in the journal Cell Reports [A. J. Kennedy, et al. (2016), Cell Rep., 16, 2666].

Key to Brush Border Assembly in the Intestine

December 2, 2016

A primary function of the lining surface of the intestine is to absorb nutrients. The epithelial cells that form this surface are notable for the presence of a brush border composed of microvilli, tiny plasma membrane projections that markedly increase the surface area through which absorption can take place. The core of each microvillus is a bundle of 20 to 30 filaments of actin protein. At the outer tip of the bundle is a cluster of proteins known as the intermicrovillar adhesion complex (IMAC). The purpose of this complex is to connect the actin bundle to cadherin proteins in the plasma membrane at the tip of the microvillus. The cadherins then link the tips of adjacent microvilli together forming a well-organized lawn. An ongoing mystery regarding microvillus formation concerns how the IMAC proteins become localized at the tip of the actin bundle. This led Vanderbilt Basic Sciences investigator Matt Tyska and his laboratory to study the role of IMAC protein myosin-7b. They found that this protein is absolutely required for IMAC organization and adhesion of adjacent microvilli. Their studies suggest that myosin-7b’s ability to use the energy from ATP hydrolysis to transport cargo proteins along an actin filament enables it to transport IMAC proteins to the tip. In addition, myosin-7b contains protein interaction domains that can bind to other IMAC proteins, retaining them in the correct location and orientation. The results show that microvilli, like similar actin filament-based structures in other tissues and organisms, depend on a myosin family protein for correct structural organization. They also provide key information to aid in our understanding of brush border morphogenesis. The work is published in the journal Current Biology [M. L. Weck, et al. (2016), Curr. Biol., ].

Targeting New Pathways for the Treatment of Schizophrenia

November 16, 2016

Although the exact cause of schizophrenia remains a mystery, accumulated evidence suggests that it is due, at least in part, to abnormal levels of the neurotransmitter dopamine in the brain. As a result, the vast majority of drugs used to treat schizophrenia block some aspect of the dopamine signaling pathway. These drugs all have serious side effects, however, leading many investigators to search for new therapeutic approaches that work by alternative mechanisms. Among these are Vanderbilt Basic Sciences researchers Jeff Conn, Carrie Jones, Craig Lindsley, and Larry Marnett. They now report that specific blockade of a receptor for the neurotransmitter acetylcholine, the M4 muscarinic receptor, produces antipsychotic effects through a novel mechanism. Earlier studies had shown that stimulation of muscarinic receptors could inhibit dopamine release in the brain, but the mechanisms for this effect were complex and not completely understood. Using a specific modulator that acts only on M4, the investigators showed that activation of this receptor results in a prolonged reduction in dopamine release. They identified the neurons in the brain responsible for this effect, and showed that they propagate the M4 signal by releasing an endocannabinoid (an endogenous compound that acts like the active ingredient of marijuana). These results define a previously unknown pathway by which dopamine neurotransmission is modulated and lay the foundation for a new approach to the treatment of schizophrenia. The availability of a drug that targets only the M4 receptor, leaving other muscarinic receptors fully functional, offers hope that this approach would be associated with fewer unwanted side effects than are observed with current antipsychotic drugs. The work is published in the journal Neuron [D. J. Foster, et al. (2016) Neuron, 91, 1244].