Regulation of hippocampal muscarinic receptor function by chronic nerve growth factor treatment in adult rats with fimbrial transections

Abstract

Effects of chronic intraventricular administration of recombinant human nerve growth factor on hippocampal muscarinic receptor densities and muscarinic receptor-linked second messenger systems were determined in adult rats 21 days following partial or full unilateral fimbrial transections. First, autoradiographic analysis of muscarinic receptors was carried out using [ 3H]quinuclidinyl benzilate for total muscarinic receptors, [ 3H]pirenzepine for M1 receptors and [ 3H]AF-DX 384 for M2 receptors. Partial fimbrial transections did not significantly alter the density of these muscarinic receptor populations in the dorsal or ventral hippocampus and there was no effect of chronic (1 /gmg every other day, 21 days) recombinant human nerve growth factor treatment. In contrast, in animals receiving full fimbrial transections which by themselves did not alter muscarinic receptor density, recombinant human nerve growth factor treatment increased the density of [ 3H]quinuclidinyl benzilate binding sites. M1 receptors, and M2 receptors by approximately 40% in the CA1 region. Secondly, we determined the effect of chronic recombinant human nerve growth factor treatment on muscarinic receptor-mediated second messenger production in rats with either partial or full unilateral fimbrial transections. In partially fimbriectomized rats, oxotremorine-induced inositol triphosphate production by hippocampal slices was increased by 81% on the lesioned side of animals treated with a control protein. This lesion-induced supersensitivity of M1 muscarinic receptor function was prevented by chronic recombinant human nerve growth factor treatment. In recombinant human nerve growth factor-treated animals, inositol triphosphate production was similar to values on unlesioned control sides. The muscarinic receptor-mediated increase in cyclic GMP levels was not altered by fimbrial transections or recombinant human nerve growth factor treatment. In animals with full unilateral fimbrial transections, oxotremorine-induced inositol triphosphate production was increased by 99% on the lesioned side of animals treated with a control protein and treatment with recombinant human nerve growth factor did not alter this denervation-induced supersensitivity of muscarinic receptor transduction signal. Chronic recombinant human nerve growth factor treatment did not affect the levels of inositol triphosphate on the contralateral unlesioned side of either partial or full fimbriectomized animals. Earlier studies indicate that chronic nerve growth factor treatment increases the presynaptic function of hippocampal cholinergic neurons surviving partial fimbrial transections. The findings of the present study indicate that these presynaptic effects translate into functional changes at the level of postsynaptic muscarinic receptors in the hippocampus. In addition, our studies suggest that a presynaptic cholinergic component is necessary to observe recombinant human nerve growth factor-induced enhancements of cholinergic receptor function in the hippocampus, since in animals receiving full unilateral transections muscarinic receptor-mediated responses are not attenuated following recombinant human nerve growth factor treatment.