Abstract
Corticotropin-releasing hormone (CRH) excites hippocampal neurons and induces death of selected CA3 pyramidal cells in immature rats. These actions of CRH require activation of specific receptors that are abundant in CA3 during early postnatal development. Given the dramatic effects of CRH on hippocampal neurons and the absence of CRH-containing afferents to this region, we hypothesized that a significant population of CRHergic neurons exists in developing rat hippocampus. This study defined and characterized hippocampal CRH-containing cells by using immunocytochemistry, ultrastructural examination, and colocalization with gamma-aminobutyric acid (GABA)-synthesizing enzyme and calcium-binding proteins. Numerous, large CRH-immunoreactive (ir) neurons were demonstrated in CA3 strata pyramidale and oriens, fewer were observed in the corresponding layers of CA1, and smaller CRH-ir cells were found in stratum lacunosum-moleculare of Ammon's horn. In the dentate gyrus, CRH-ir somata resided in the granule cell layer and hilus. Ultrastructurally, CRH-ir neurons had aspiny dendrites and were postsynaptic to both asymmetric and symmetric synapses. CRH-ir axon terminals formed axosomatic and axodendritic symmetric synapses with pyramidal and granule cells. Other CRH-ir terminals synapsed on axon initial segments of principal neurons. Most CRH-ir neurons were coimmunolabeled for glutamate decarboxylase (GAD)-65 and GAD-67 and the majority also contained parvalbumin, but none were labeled for calbindin. These results confirm the identity of hippocampal CRH-ir cells as GABAergic interneurons. Further, a subpopulation of neurons immunoreactive for both CRH and parvalbumin and located within and adjacent to the principal cell layers consists of basket and chandelier cells. Thus, axon terminals of CRH-ir interneurons are strategically positioned to influence the excitability of the principal hippocampal neurons via release of both CRH and GABA.
Highlights
Corticotropin-releasing hormone (CRH) is a neuropeptide with both neuroendocrine and neurotransmitter properties (Vale et al, 1981; Young, 1992)
We aimed to define the neuroanatomical features of these neurons by using both light and electron microscopic (EM) methods and to study the colocalization of CRH with glutamate decarboxylase (GAD) and calcium-binding proteins
In the dentate gyrus itself, CRH-ir cell bodies were mainly found in the granule cell layer and the hilus (Fig. 1)
Summary
Corticotropin-releasing hormone (CRH) is a neuropeptide with both neuroendocrine and neurotransmitter properties (Vale et al, 1981; Young, 1992). The neuroendocrine effects of CRH, the key mediator of the stress response, originate from clusters of peptidergic cells in the hypothalamic paraventricular nucleus (Lightman and Harbuz, 1993; Herman and Cullinan, 1997). CRH-producing neurons are widely but distributed in the brain (Sawchenko et al, 1993), including the central nucleus of the amygdala, which is considered a major source for nonendocrine CRH-mediated neurotransmission (Herman and Cullinan, 1997). Target neurons for CRH, expressing specific receptors, are found in brain regions including the hippocampus (Chalmers et al, 1995; Avishai-Eliner et al, 1996). Physiological effects of CRH on hippocampal neurons include facilitating memory retention and increasing protein phosphorylation (Lee et al, 1992; Behan et al, 1995). Abnormalities of CRH-mediated neurotransmission may contribute to neurological disorders such as depression (Nemeroff, 1992) or Alzheimer's disease (Behan et al, 1995)
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