Edward Korzus

CBP histone acetyltransferase activity is a critical component of memory consolidation.

The stabilization of learned information into long-term memories requires new gene expression. CREB binding protein (CBP) is a coactivator of transcription that can be independently regulated in neurons. CBP functions both as a platform for recruiting other required components of the transcriptional machinery and as a histone acetyltransferase (HAT) that alters chromatin structure. To dissect the chromatin remodeling versus platform function of CBP or the developmental versus adult role of this gene, we generated transgenic mice that express CBP in which HAT activity is eliminated. Acquisition of new information and short-term memory is spared in these mice, while the stabilization of short-term memory into long-term memory is impaired. The behavioral phenotype is due to an acute requirement for CBP HAT activity in the adult as it is rescued by both suppression of transgene expression or by administration of the histone deacetylase inhibitor Trichostatin A (TSA) in adult animals.

Signal-specific co-activator domain requirements for Pit-1 activation

POU-domain proteins, such as the pituitary-specific factor Pit-1, are members of the homeodomain family of proteins which are important in development and homeostasis, acting constitutively or in response to signal-transduction pathways to either repress or activate the expression of specific genes. Here we show that whereas homeodomain-containing repressors such as Rpx seem to recruit only a co-repressor complex, the activity of Pit-1 (ref. 3) is determined by a regulated balance between a co-repressor complex that contains N-CoR/SMRT,, mSin3A/B and histone deacetylases and a co-activator complex that includes the CREB-binding protein (CBP) and p/CAF. Activation of Pit-1 by cyclic AMP or growth factors depends on distinct amino- and carboxy-terminal domains of CBP, respectively. Furthermore, thehistone acetyltransferase functions of CBP, or p/CAF are required for Pit-1 function that is stimulated by cyclic AMP or growth factors, respectively. These data show that there is a switch in specific requirements for histone acetyltransferases and CBP domains in mediating the effects of different signal-transduction pathways on specific DNA-bound transcription factors.

Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system

Neuregulin-1 (NRG1) and its ErbB2/B4 receptors are encoded by candidate susceptibility genes for schizophrenia, yet the essential functions of NRG1 signaling in the CNS are still unclear. Using CRE/LOX technology, we have inactivated ErbB2/B4-mediated NRG1 signaling specifically in the CNS. In contrast to expectations, cell layers in the cerebral cortex, hippocampus, and cerebellum develop normally in the mutant mice. Instead, loss of ErbB2/B4 impairs dendritic spine maturation and perturbs interactions of postsynaptic scaffold proteins with glutamate receptors. Conversely, increased NRG1 levels promote spine maturation. ErbB2/B4-deficient mice show increased aggression and reduced prepulse inhibition. Treatment with the antipsychotic drug clozapine reverses the behavioral and spine defects. We conclude that ErbB2/B4-mediated NRG1 signaling modulates dendritic spine maturation, and that defects at glutamatergic synapses likely contribute to the behavioral abnormalities in ErbB2/B4-deficient mice.

Epigenetic Mechanisms and Gene Networks in the Nervous System

Adaptation to the environment is one of the fundamental regulatory processes in biology and is found among both simple and complex organisms. In a changing environment, simple organisms enhance species survival by high rates of spontaneous mutation achieved by several means: short maturation rates,

Nuclear Calcium/Calmodulin Regulates Memory Consolidation

The neuronal response to a Ca2+ stimulus is a complex process involving direct Ca2+/calmodulin (CaM) actions as well as secondary activation of multiple signaling pathways such as cAMP and ERK (extracellular signal-regulated kinase). These signals can act in both the cytoplasm and the nucleus to control gene expression. To dissect the role of nuclear from cytoplasmic Ca2+/CaM signaling in memory formation, we generated transgenic mice that express a dominant inhibitor of Ca2+/CaM selectively in the nuclei of forebrain neurons and only after the animals reach adulthood. These mice showed diminished neuronal activity-induced phosphorylation of cAMP response element-binding protein, reduced expression of activity-induced genes, altered maximum levels of hippocampal long-term potentiation, and severely impaired formation of long-term, but not short-term, memory. Our results demonstrate that nuclear Ca2+/CaM signaling plays a critical role in memory consolidation in the mouse.

GLT-1-Dependent Disruption of CNS Glutamate Homeostasis and Neuronal Function by the Protozoan Parasite Toxoplasma gondii

The immune privileged nature of the CNS can make it vulnerable to chronic and latent infections. Little is known about the effects of lifelong brain infections, and thus inflammation, on the neurological health of the host. Toxoplasma gondii is a parasite that can infect any mammalian nucleated cell with average worldwide seroprevalence rates of 30%. Infection by Toxoplasma is characterized by the lifelong presence of parasitic cysts within neurons in the brain, requiring a competent immune system to prevent parasite reactivation and encephalitis. In the immunocompetent individual, Toxoplasma infection is largely asymptomatic, however many recent studies suggest a strong correlation with certain neurodegenerative and psychiatric disorders. Here, we demonstrate a significant reduction in the primary astrocytic glutamate transporter, GLT-1, following infection with Toxoplasma. Using microdialysis of the murine frontal cortex over the course of infection, a significant increase in extracellular concentrations of glutamate is observed. Consistent with glutamate dysregulation, analysis of neurons reveal changes in morphology including a reduction in dendritic spines, VGlut1 and NeuN immunoreactivity. Furthermore, behavioral testing and EEG recordings point to significant changes in neuronal output. Finally, these changes in neuronal connectivity are dependent on infection-induced downregulation of GLT-1 as treatment with the ß-lactam antibiotic ceftriaxone, rescues extracellular glutamate concentrations, neuronal pathology and function. Altogether, these data demonstrate that following an infection with T. gondii, the delicate regulation of glutamate by astrocytes is disrupted and accounts for a range of deficits observed in chronic infection.

Manipulating the brain with epigenetics

A study finds that the DNA methylation enzymes Dnmt1 and Dnmt3a are needed to maintain the epigenetic landscape in nondividing, postmitotic neurons and that this process is required for normal learning and memory.

An animal model of female adolescent cannabinoid exposure elicits a long-lasting deficit in presynaptic long-term plasticity

Cannabis continues to be the most accessible and popular illicit recreational drug. Whereas current data link adolescence cannabinoid exposure to increased risk for dependence on other drugs, depression, anxiety disorders and psychosis, the mechanism(s) underlying these adverse effects remains controversial. Here we show in a mouse model of female adolescent cannabinoid exposure deficient endocannabinoid (eCB)-mediated signaling and presynaptic forms of long-term depression at adult central glutamatergic synapses in the prefrontal cortex. Increasing endocannabinoid levels by blockade of monoacylglycerol lipase, the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG), with the specific inhibitor JZL 184 ameliorates eCB-LTD deficits. The observed deficit in cortical presynaptic signaling may represent a neural maladaptation underlying network instability and abnormal cognitive functioning. Our study suggests that adolescent cannabinoid exposure may permanently impair brain functions, including the brains intrinsic ability to appropriately adapt to external influences.

Prefrontal NMDA receptors expressed in excitatory neurons control fear discrimination and fear extinction.

N-methyl-D-aspartate receptors (NMDARs) are critically involved in various learning mechanisms including modulation of fear memory, brain development and brain disorders. While NMDARs mediate opposite effects on medial prefrontal cortex (mPFC) interneurons and excitatory neurons, NMDAR antagonists trigger profound cortical activation. The objectives of the present study were to determine the involvement of NMDARs expressed specifically in excitatory neurons in mPFC-dependent adaptive behaviors, specifically fear discrimination and fear extinction. To achieve this, we tested mice with locally deleted Grin1 gene encoding the obligatory NR1 subunit of the NMDAR from prefrontal CamKIIα positive neurons for their ability to distinguish frequency modulated (FM) tones in fear discrimination test. We demonstrated that NMDAR-dependent signaling in the mPFC is critical for effective fear discrimination following initial generalization of conditioned fear. While mice with deficient NMDARs in prefrontal excitatory neurons maintain normal responses to a dangerous fear-conditioned stimulus, they exhibit abnormal generalization decrement. These studies provide evidence that NMDAR-dependent neural signaling in the mPFC is a component of a neural mechanism for disambiguating the meaning of fear signals and supports discriminative fear learning by retaining proper gating information, viz. both dangerous and harmless cues. We also found that selective deletion of NMDARs from excitatory neurons in the mPFC leads to a deficit in fear extinction of auditory conditioned stimuli. These studies suggest that prefrontal NMDARs expressed in excitatory neurons are involved in adaptive behavior.

Impaired Fear Memory Specificity Associated with Deficient Endocannabinoid-Dependent Long-Term Plasticity

In addition to its central role in learning and memory, N-methyl D-aspartate receptor (NMDAR)-dependent signaling regulates central glutamatergic synapse maturation and has been implicated in schizophrenia. We have transiently induced NMDAR hypofunction in infant mice during postnatal days 7–11, followed by testing fear memory specificity and presynaptic plasticity in the prefrontal cortex (PFC) in adult mice. We show that transient NMDAR hypofunction during early brain development, coinciding with the maturation of cortical plasticity results in a loss of an endocannabinoid (eCB)-mediated form of long-term depression (eCB-LTD) at adult central glutamatergic synapses, while another form of presynaptic long-term depression mediated by the metabotropic glutamate receptor 2/3 (mGluR2/3-LTD) remains intact. Mice with this selective impairment of presynaptic plasticity also showed deficits in fear memory specificity. The observed deficit in cortical presynaptic plasticity may represent a neural maladaptation contributing to network instability and abnormal cognitive functioning.