Deficits in LTP and recognition memory in the genetically hypertensive rat are associated with decreased expression of neurotrophic factors and their receptors in the dentate gyrus

Abstract

We have previously reported that a genetically hypertensive strain of Wistar rat (GH), is deficient in nerve growth factor (NGF) and Trk receptors in dentate gyrus and that these deficits are accompanied by impaired expression of long-term potentiation (LTP) in perforant path–granule cell synapses. Here we confirm this deficit in LTP and report that this strain of rat also displays impairments in long-term recognition memory when compared with normotensive controls. Further analysis of neurotrophin expression in dentate gyrus confirmed the previously-reported deficit in NGF and revealed a decrease in expression of brain-derived neurotrophic factor (BDNF), but not neurotrophin 3 (NT3) or neurotrophin 4 (NT4), in GH rats. These alterations in ligand expression were accompanied by changes in Trk receptor expression; specifically, a decrease in expression of TrkA and TrkB, but not TrkC, in the dentate gyrus of GH, compared with normotensive, rats. We conclude that the impairments in LTP and learning and memory observed in the GH strain are associated with aberrant expression of specific neurotrophic factors and their receptors in the dentate gyrus, adding weight to the evidence indicating a role for these proteins in several forms of synaptic plasticity.

Introduction

The roles of neurotrophins in hippocampal synaptic plasticity have been extensively investigated for over a decade. The members of this family of proteins known to be expressed in the mammalian brain include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4). All neurotrophins bind with low affinity to the p75NTR receptor [16], and each binds preferentially and with high affinity to different isoforms of the Trk receptor family; TrkA preferentially binds NGF, TrkB preferentially binds BDNF and NT4, while NT3 is the preferred ligand of TrkC [34]. Trk receptor activation results in activation of a number of signalling cascades that have been associated with expression of synaptic plasticity, including the mitogen-activated protein kinase (MAPK) [38] and phosphatidylinositol 3’-kinase (PI3K)/Akt pathways [1]. It is thus unsurprising that neurotrophins have been suggested to play fundamental roles in such processes as long-term potentiation (LTP; e.g., [4], [5], [6], [22]), and a variety of learning tasks (e.g., [7], [32], [19]).

Each of the neurotrophins and their receptors is expressed differentially in the hippocampus, with all being expressed to a greater or lesser extent in the dentate gyrus subfield [2]. Evidence exists to suggest a role for each of the neurotrophins in various forms of hippocampal plasticity. There is particularly compelling evidence for such functions for NGF and BDNF both from our laboratory [23], [24], [32] and others; for example, mice deficient in BDNF show impairments in object recognition and spatial learning [18] and in LTP in area CA1 of the hippocampus [27] that can be reversed by BDNF treatment [33], while NGF has been proposed to play a role in both contextual memory consolidation [42] and spatial learning [15]. There is less evidence indicating the involvement of NT3 and NT4 in hippocampal plasticity, although NT4-deficient mice have been reported to show impairments in long-term memory and in LTP in CA1 [43] and conditional NT3 knockout mice have recently been reported to display decreased neurogenesis in dentate gyrus, concomitant with impaired spatial learning and LTP [36].

While transgenic mice have proven to be a useful experimental tool, the genetically hypertensive (GH) inbred strain of rat provides another potential model with which to examine the effect of lack of neurotrophins and/or their receptors on neuronal function. The first indication of such a possibility came from a report that observed a deficit in NGF availability in the peripheral nervous system of the GH rat [28]. We subsequently extended this finding to the central nervous system, observing a decrease in expression and activity-dependent release of NGF and expression of Trk receptors in the dentate gyrus of the GH rat that was accompanied by impaired expression of LTP [21]. Since a non-specific pan-Trk antibody was used in these experiments, we did not identify whether or not expression of all Trk isoforms was altered in the GH rat.

In this study, we have extended our study of the GH strain of rat by examining the ability of the GH rat to perform a hippocampal-dependent learning task, long-term object recognition, that we have suggested may rely upon NGF-stimulated intracellular signalling [19]. We have also investigated whether the impairments in hippocampal function displayed by these rats are accompanied by alterations in expression of other neurotrophins and their receptors.