Hippocampal plasticity involves extensive gene induction and multiple cellular mechanisms

Abstract

Long-term plasticity of the central nervous system (CNS) involves induction of a set of genes whose identity is incompletely characterized. To identify candidate plasticity-related genes (CPGs), we conducted an exhaustive screen for genes that undergo induction or downregulation in the hippocampus dentate gyrus (DG) following animal treatment with the potent glutamate analog, kainate. The screen yielded 362 upregulated CPGs and 41 downregulated transcripts (dCPGs). Of these, 66 CPGs and 5 dCPGs are known genes that encode for a variety of signal transduction proteins, transcription factors, and structural proteins. Seven novel CPGs predict the following putative functions: cpg2--a dystrophin-like cytoskeletal protein; cpg4--a heat-shock protein: cpg16--a protein kinase; cpg20--a transcription factor; cpg21--a dual-specificity MAP-kinase phosphatase; and cpg30 and cpg38--two new seven-transmembrane domain receptors. Experiments performed in vitro and with cultured hippocampal cells confirmed the ability of the cpg-21 product to inactivate the MAP-kinase. To test relevance to neural plasticity, 66 CPGs were tested for induction by stimuli producing long-term potentiation (LTP). Approximately one-fourth of the genes examined were upregulated by LTP. These results indicate that an extensive genetic response is induced in mammalian brain after glutamate receptor activation, and imply that a significant proportion of this activity is coinduced by LTP. Based on the identified CPGs, it is conceivable that multiple cellular mechanisms underlie long-term plasticity of the nervous system.

The Neuropeptide VGF Produces Antidepressant-Like Behavioral Effects and Enhances Proliferation in the Hippocampus

“…The VGF gene has a CREB binding site, which is necessary for its induction by other neurotrophic factors (Salton et al, 2000), and suggests a point of convergence for transcriptional regulation by 5-HT and BDNF. Furthermore, expression of VGF is induced by BDNF (Eagleson et al, 2001;Alder et al, 2003) as well as in models of neuronal activity such as learning, LTP, seizure, and synaptogenesis (Lombardo et al, 1995;Benson and Salton, 1996;Hevroni et al, 1998;Snyder et al, 1998;Alder et al, 2003;Newton et al, 2003;Altar et al, 2004). In support of our findings of an increase in VGF expression after imipramine treatment, an increase in VGF mRNA was observed in the hippocampus of animals after electroconvulsive therapy (Newton et al, 2003;Altar et al, 2004;Conti et al, 2007).…”

BICC1 Expression is Elevated in Depressed Subjects and Contributes to Depressive Behavior in Rodents

“…However, the exact mechanisms for the rapid and robust downregulation of BICC1 mRNA in BICC1 expression is elevated in depressed subjects KT Ota et al response to ketamine and KCl treatment will require additional studies. The activity-dependent downregulation of BICC1 is particularly interesting as genes showing activityinduced downregulation are relatively rare: they are an order of magnitude lower in abundance than genes showing activity-dependent upregulation (Hevroni et al, 1998;West et al, 2002). Here, we also show that the downregulation of BICC1 is functionally relevant, as knockdown of BICC1 in the hippocampus is sufficient to rescue anhedonic behavior in CUS-treated rats.…”

Both Doublecortin and Doublecortin-Like Kinase Play a Role in Cortical Interneuron Migration

“…The two genes show overlapping expression patterns, although DCLK is more widely expressed in the brain (Sossey-Alaoui and Srivastava, 1999;Burgess and Reiner, 2000). In addition, DCLK encodes multiple transcripts, which are all differently regulated and may have different functions (Hevroni et al, 1998;Burgess et al, 1999;Silverman et al, 1999;Vreugdenhil et al, 2001;Burgess and Reiner, 2002). Two groups have recently reported that, although Dcx or Dclk mutant mice do not show defects in radial neuronal migration, mutants for both Dcx and Dclk genes display cortical lamination defects, suggesting that they can functionally compensate each other (Deuel et al, 2006;Koizumi et al, 2006a).…”