Effects of Neurotrophins on Synaptic Protein Expression in the Visual Cortex of Dark-Reared Rats

Abstract

Total lack of visual experience [dark rearing (DR)] is known to prolong the critical period and delay development of sensory functions in mammalian visual cortex. Recent results show that neurotrophins (NTs) counteract the effects of DR on functional properties of visual cortical cells and exert a strong control on critical period duration. NTs are known to modulate the development and synaptic efficacy of neurotransmitter systems that are affected by DR. However, it is still unknown whether the actions of NTs in dark-reared animals involve interaction with neurotransmitter systems. We have studied the effects of DR on the expression of key molecules in the glutamatergic and GABAergic systems in control and NT-treated animals. We have found that DR reduced the expression of the NMDA receptor 2A subunit and its associated protein PSD-95 (postsynaptic density-95), of GRIP (AMPA glutamate receptor interacting protein), and of the biosynthetic enzyme GAD (glutamic acid decarboxylase). Returning dark-reared animals to light for 2 hr restored normal expression of the above-mentioned proteins almost completely. NT treatment specifically counteracts DR effects; NGF acts primarily on the NMDA system, whereas BDNF acts primarily on the GABAergic system. Finally, the action of NT4 seems to involve both excitatory and inhibitory systems. These data demonstrate that different NTs counteract DR effects by modulating the expression of key molecules of the excitatory and inhibitory neurotransmitter systems.

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

“…4 Structure-activity studies revealed that peptides containing the highly hydrophobic 25-35 region formed stable aggregates and mediated neuronal death by necrosis or apoptosis. 5,6,7 The truncated A␤ [25][26][27][28][29][30][31][32][33][34][35] fragment includes extracellular and intramembrane residues that have been reported to represent an active region of A␤. 8 In vivo, two nontransgenic rodent models of AD have been studied to analyze the molecular, morphological, and behavioral consequences of amyloid toxicity: the infusion of A␤ 1-40/42 protein and the injection of preaggregated A␤ [25][26][27][28][29][30][31][32][33][34][35] peptide.…”

“…These models have led to highly pertinent pathomimetic observations and provide complementary approaches to the numerous transgenic mouse lines developed as AD models. In particular, at 1 week after A␤ [25][26][27][28][29][30][31][32][33][34][35] injection, reactive gliosis was observed in the rat hippocampus, 9 caspase-3 activity was induced in the hippocampus and cortex, 9 a reduction in the number of neurons was measured in the CA1 or CA3 hippocampal area, 9 -11 and significant oxidative stress was observed. [11][12][13] Nonetheless, this amyloid toxicity model remains controversial with respect to AD.…”

“…First, although the presence of A␤ [25][26][27][28][29][30][31][32][33][34][35] has been repeatedly demonstrated in brains of AD patients, 14,15 this fragment appears to be a minor peptide in plaques and its contribution to the toxicity induced by all amyloid-related species remains unclear. Second, the intracerebroventricular injection of A␤ [25][26][27][28][29][30][31][32][33][34][35] induces marked toxicity within days or weeks, which is not in accord with the long-term progression of AD in humans (an argument that is unrelated to the nature of the toxicity). Third, it is possible that peptide injection mimics only the amyloid toxicity observed in AD physiopathology, but not the processes involved in A␤ formation or Tau protein hyperphosphorylation.…”

“…Klementiev et al 16 recently documented some evidence that contradicts this latter reservation. Moreover, very recently, Chavant et al 17 reported that, at 2 weeks after injection, A␤ [25][26][27][28][29][30][31][32][33][34][35] significantly increased APP processing in the hippocampus of mice.…”

“…We therefore analyzed the consequences of intracerebroventricular injection of aggregated A␤ [25][26][27][28][29][30][31][32][33][34][35] in terms of time-course changes and in different brain structures through several morphological, hormonal, biochemical, and behavioral parameters, as well as addressing the modifications in central APP processing, brain-derived neurotrophic factor (BDNF) levels, cerebral inflammation, and hippocampus vulnerability. We also evaluated over time the distribution within brain structures of the injected A␤ [25][26][27][28][29][30][31][32][33][34][35] fragment.…”