Regulation of muscarinic receptors in hippocampus following cholinergic denervation and reinnervation by septal and striatal transplants

Abstract

The regulation of hippocampal muscarinic M1 and M2 receptors was studied by autoradiographic methods following cholinergic denervation and reinnervation from embryonic septal transplant. In young adult male rats the density of M1 sites, labeled either with 3H-pirenzepine (PZ) or 3H-N-methylscopolamine (NMS, in the presence of excess carbachol), exceeded by 4- to 5-fold the density of M2 sites, labeled with 3H-NMS in the presence of excess PZ. Both receptors appeared to be densest in hippocampal regions lowest in acetylcholinesterase or 3H-hemicholinium-3 binding. The distribution of M1 receptors did differ from the distribution of M2 receptors within subregions of the hippocampus. Along the mediolateral axis from the subiculum to the lateral CA 1, the density of M1 receptors is uniform, but the density of M2 receptors decreases. Also apparent is the relatively small difference in density between the CA1 and dentate gyrus for M1 receptors but a significantly greater difference for M2 receptors. However, the response of M1 and M2 receptors to long-term cholinergic denervation following fimbriafornix transection of the septal cholinergic input and to cholinergic innervation by embryonic septal transplants was similar. Long-term denervation (40-60 d) resulted in a 30-60% increase in both M1 and M2 receptors within regions of the hippocampal formation. Receptor levels were reduced to normal in regions innervated by septal transplants. For both receptors, the changes in the density of sites were due to alterations in the Bmax and not the Kd for the radioligands. The specificity of this regulation is supported by the evidence that (1) the degree and topography of the normalization of muscarinic receptor density was entirely dependent on the degree and pattern of cholinergic reinnervation by the fibers of the septal transplant, (2) cholinergic fiber reinnervation by embryonic striatal grafts also down-regulated the density of M1 and M2 receptors, and (3) successfully surviving transplants (e.g., cerebellar and striatal) that did not provide innervation to the hippocampus did not induce down-regulation of muscarinic receptors. Changes in the density of sites were not related to changes in the width of the hippocampus following denervation and reinnervation. The data support the view that the majority of M1 and M2 receptors are located postsynaptically on neurons within the hippocampus and not presynaptically on cholinergic fibers.

Hippocampal sympathetic ingrowth and cholinergic denervation alter hippocampal muscarinic cholinergic receptors

“…However, by assessing the dorsal and ventral regions independently, we have demonstrated that cholinergic denervation induces changes in the mAChR. This finding is further supported by autoradiographic studies (Dawson et al, 1989;Joyce et al, 1989), as well as homogenate binding studies confined to the dorsal hippocampus (Westlind et al, 1981;Ulas et al, 1987). in which increased numbers, without change in affinity, of mAChR have been found in the dorsal hippocampus after MS or fimbria-fornix lesions.…”

Endogenous ACh effects on NMDA‐induced interictal‐like discharges along the septotemporal hippocampal axis of adult rats and their modulation by an early life generalized seizure

“…The more intense and persistent IED frequency potentiation in the PTZ‐septal slices (Fig. 2A,C) might be explained by the more effective coupling of muscarinic receptors with G proteins following an early seizure (Potier et al., 2005) combined with the increased availability of endogenous ACh in the septal hippocampus (because of the stronger fimbria‐fornix cholinergic‐muscarinic input there (Wyss et al., 1980; Nicoll, 1985; Joyce et al., 1989; Wall et al., 2008)).…”

“…Extracellular ACh increase (by eserine) had the most profound effect on IED frequency in PTZ‐septal slices. The septal hippocampal‐parahippocampal connectivity (Dolorfo & Amaral, 1998; Delatour & Witter, 2002; Kerr et al., 2007), with its relatively stronger fimbria‐fornix muscarinic input (Wyss et al., 1980; Nicoll, 1985; Joyce et al., 1989; Wall et al., 2008) suggests that a local transient ACh overflow in a conditioned subject (i.e., a subject with a history of early life sustained generalized seizures) would increase IED output to the entorhinal cortex, which might then be further amplified within the hippocampal‐entorhinal cortex loop (Chrobak & Buzsaki, 1994; Chrobak et al., 2000). This in turn might contribute to a transient disruption of memory function (Zhou et al., 2007; Kleen et al., 2010) as indeed has been suggested for interictal spiking (Binnie, 2003; Pressler et al., 2005).…”

Cholinergic Deafferentation of Dorsal Hippocampus by Fimbria‐Fornix Lesioning Differentially Regulates Subtypes (m1‐m5) of Muscarinic Receptors

“…In contrast, laboratories that limited their examinations to the dorsal hippocampal formation subsequent to lesioning of the medial septum reported increases in muscarinic receptor levels of 18% (Kaseda et al, 1989) and 20% (Westlind et al,198 1). By using autoradiographic techniques, larger increases (30-80%) in receptor expression were observed within areas CA2, CA3, CA4, and the stratum oriens of the hippocampal formation following fimbria-fornix lesioning, or after injection of the cholinergic toxin AF64A into the medial septa1 nucleus (Dawson et al, 1989;Joyce et al, 1989;Dawson and Wamsley, 1990;Zang et al, 1992).…”