Long-term potentiation activates the GAP-43 promoter: Selective participation of hippocampal mossy cells

Abstract

Perforant path long-term potentiation (LTP) in intact mouse hippocampal dentate gyrus increased the neuron-specific, growth-associated protein GAP-43 mRNA in hilar cells 3 days after tetanus, but surprisingly not in granule cells While it is now well established that long-term potentiation (LTP), a physiological model of the memory storage process, activates immediate early genes encoding transcription factors (1, 2), there is no evidence to our knowledge indicating what target genes are activated by these transcription factors. GAP-43, ¶ the presynaptically localized, growth-associated protein whose expression is up-regulated during axonal outgrowth in development and axonal regeneration (3), and whose phosphorylation is increased after LTP (4), is one likely candidate target gene (see also ref. 5). A previous study of chronic recording in intact freely moving rats 3 days after LTP induction revealed that perforant path LTP altered GAP-43 mRNA expression (6). To explore the hypothesis that the alteration in GAP-43 mRNA was related to altered transcriptional activity of the GAP-43 gene in hippocampal neurons after LTP, we first studied the effect of LTP in the intact mouse on the endogenous pattern of GAP-43 mRNA transcript levels with in situ hybridization. We then studied the effect of LTP on promoter activation in transgenic mice bearing a GAP-43 promoter-lacZ reporter construct. MATERIALS AND METHODSAnimals. Mouse strain C57BL͞6 was obtained from The Jackson Laboratory. Heterozygous GAP-43͞lacZ transgenic mouse line 252 bearing 6-kb 5Ј-flanking and 11-kb first intron sequence driving lacZ reporter gene was bred with C57BL͞6 mice, and homozygous transgenic mice were initially screened by genomic DNA Southern or dot hybridization. Constitutive expression of the transgene in hippocampus in GAP-43͞lacZ transgenic mouse line 252 has been described (7, 8). Thirty-five male homozygous transgenic mice (2 months old) were used in the electrophysiological and histochemical analysis.Electrophysiology. In vivo LTP in anesthetized mice was performed essentially as described previously (9). Potentiated responses were measured by percent baseline population spike amplitude. Mean potentiation of combined 1-, 2-, and 3-day LTP group animals was 255% Ϯ 40.1% (n ϭ 20; mean Ϯ SEM) over the 2-hr recording session and did not show any significant difference from that of wild-type C57BL͞6 mice (229.4% Ϯ 36.3%, P Ͼ 0.10). Mean response of the low-frequency control (LFC) animals during the 2-hr recording period was 101.1 Ϯ 5.5 (n ϭ 15). In the LTP experiment with DL-aminophosphonovalerate (APV; Sigma) ejection, 80 nl (1.6 nmol) of APV dissolved in 20 mM Tris⅐HCl (pH 8.0) was pressure-ejected from the recording micropipette into the dentate gyrus molecular layer, using procedures described earlier (10). APV was delivered 15 min prior to high-frequency tetanic stimulation. Equivalent volumes of 20 mM Tris vehicle were ejected into the same region of the hippocampus in control group animals. Potentiated responses in the molecul...

Poly(A) Tail Length-dependent Stabilization of GAP-43 mRNA by the RNA-binding Protein HuD

“…Transcriptional factors of the basic helix-loop-helix family are known to control the neural specific expression of the GAP-43 gene (12,13). Yet, and most surprisingly, in several instances, the levels of gene transcription do not correlate well with the accumulation of the mature GAP-43 mRNA (8,9,11,14,15). In PC12 cells induced to differentiate by nerve growth factor, GAP-43 mRNA levels are regulated primarily through selective changes in the rate of degradation of the mRNA (9).…”

Mice Deficient in Collapsin Response Mediator Protein-1 Exhibit Impaired Long-Term Potentiation and Impaired Spatial Learning and Memory

“…Meanwhile, GAP-43 is presynaptically localized and its expression is upregulated during axonal outgrowth (Benowitz and Routtenberg, 1997). Transcription and phosphorylation of GAP-43 are increased after LTP (Lovinger et al, 1985), and manipulating GAP-43 levels can alter LTP and regulate synaptic enhancement (Namgung et al, 1997). Because hippocampal dendritic spine density reflects the number of excitatory synapses per neuron associated with learning (Moser et al, 1994), we posit that reduction of hippocampal PSD95 and GAP-43 represent a reduction of dendritic spine density associated with impaired neuronal plasticity, which in turn may contribute to cognitive deficits.…”

GAP-43 in synaptic plasticity: molecular perspectives

“…92 Perforant path LTP in the intact mouse hippocampal dentate gyrus increased GAP-43 mRNA in hilar cells 3 days after tetanus, but not in granule cells. 93 The LTP-induced GAP-43 mRNA elevation in hilar cells was positively correlated with the level of potentiation and blocked by pretreatment with the NMDA receptor antagonist, DL-aminophosphonovalerate. 93 The phosphorylation state of GAP-43 was monitored after induction of LTP in the CA1 field in rat hippocampal slices and revealed increased phosphorylation 10-60 minutes following LTP induction but not after 90 minutes.…”

“…93 The LTP-induced GAP-43 mRNA elevation in hilar cells was positively correlated with the level of potentiation and blocked by pretreatment with the NMDA receptor antagonist, DL-aminophosphonovalerate. 93 The phosphorylation state of GAP-43 was monitored after induction of LTP in the CA1 field in rat hippocampal slices and revealed increased phosphorylation 10-60 minutes following LTP induction but not after 90 minutes. 94 The increased GAP-43 phosphorylation was not observed when LTP was blocked with DL-aminophosphonovalerate or when tetanic stimulation failed to induce LTP.…”