Abstract
Within the cortex, nerve growth factor (NGF) mediates the innervation of cholinergic neurons during development, maintains cholinergic corticopetal projections during adulthood and modulates cholinergic function through phenotypic control of the cholinergic gene locus. Recent studies suggest NGF may also play an important role in cortical plasticity in adulthood. Previously, NGF-producing cells have been shown to colocalize with GABAergic cell markers within the hippocampus, striatum, and basal forebrain. Classification of cells producing NGF in the cortex is lacking, however, and cholinergic corticopetal projections have been shown to innervate both pyramidal and GABAergic neurons in the cortex. In order to clarify potential trophic interactions between cortical neurons and cholinergic projections, we used double-fluorescent immunohistochemistry to classify NGF-expressing cells in several cortical regions, including the prefrontal cortex, primary motor cortex, parietal cortex and temporal cortex. Our results show that NGF colocalizes extensively with GABAergic cell markers in all cortical regions examined, with >91% of NGF-labeled cells coexpressing GAD65/67. Conversely, NGF-labeled cells exhibit very little co-localization with the excitatory cell marker CaMKIIα (<5% of cells expressing NGF). NGF expression was present in 56% of GAD-labeled cells, suggesting that production is confined to a specific subset of GABAergic neurons. These findings demonstrate that GABAergic cells are the primary source of NGF production in the cortex, and likely support the maintenance and function of basal forebrain cholinergic projections in adulthood.
Highlights
The neurotrophin nerve growth factor (NGF) is involved in several critical processes in the developing and mature mammalian nervous system, including target innervation, cell differentiation and neuronal survival (Large et al, 1986; Li et al, 1995; Sofroniew et al, 2001; Lad et al, 2003)
We identify a subset of cortical GABAergic cells as the primary source of NGF production in the adult cortex, with relatively rare production by glutamatergic neurons
The current study demonstrates that the vast majority (>90%) of NGF-producing neurons of the cortex are GABAergic, while half of all GABAergic neurons colocalize with NGF
Summary
The neurotrophin nerve growth factor (NGF) is involved in several critical processes in the developing and mature mammalian nervous system, including target innervation, cell differentiation and neuronal survival (Large et al, 1986; Li et al, 1995; Sofroniew et al, 2001; Lad et al, 2003). The basal forebrain cholinergic system influences learning and experience-dependent plasticity in the cortex (Bakin and Weinberger, 1996; Kilgard and Merzenich, 1998; Conner et al, 2003, 2005), and NGF signaling has been hypothesized to support, and possibly enhance, basal forebrain-mediated learning and plasticity. A recent study by Conner et al (2009) demonstrated that both spatial learning and hippocampal long-term potentiation (LTP) are enhanced following infusions of NGF into the septal nucleus, the primary source of cholinergic innervation to the hippocampus
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