Modulation Of Neuronal Channels and Receptors in the Brain

National Institute Of Environmental Health Sciences

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Abstract

There have been several major accomplishments within the past fiscal year. The dentate gyrus (DG) is a unique brain structure in that neurons can be generated postnatally and integrated within existing circuitry throughout life. The maturation process of these newly generated neurons (granule cells) is modulated by nicotinic acetylcholine receptors (nAChRs) through a variety of mechanisms such as neural stem pool proliferation, cell survival, signal modulation, and dendritic integration. Disrupted nAChR signaling has been implicated in neuropsychiatric and neurodegenerative disorders, potentially via alterations in DG neurogenesis. GABAergic interneurons are known to express nAChRs, predominantly the 7 subtype, and have been shown to shape development, integration, and circuit reorganization of DG granule cells. Therefore, we examined histological and behavioral effects of knocking out 7 nAChRs in GABAergic neurons. Deletion of 7 nAChRs resulted in a reduction of radial glia-like cells within the subgranular zone of the DG and a concomitant trend towards decreased immature neurons, specifically in male mice, as well as sex-dependent changes in several behaviors, including social recognition and spatial learning. Overall, these findings suggest 7 nAChRs expressed in GABAergic neurons play an important role in regulating the adult neural stem cell pool and behavior in a sex-dependent manner. This provides important insight into the mechanisms by which cholinergic dysfunction contributes to the cognitive and behavioral changes associated with neurodevelopmental and neurodegenerative disorders. In addition, the medial septum/diagonal band of Broca (MS/DBB) receives direct GABAergic input from the hippocampus via hippocamposeptal (HS) projection neurons as part of a reciprocal loop that mediates cognition and is altered in Alzheimer's disease. Cholinergic and GABAergic interactions occur throughout the MS/DBB, but it is not known how HS GABA release is impacted by these circuits. Most HS neurons contain somatostatin (SST), so to evoke HS GABA release we expressed Cre-dependent mCherry/channelrhodopisin-2 (ChR2) in the hippocampi of SST-IRES-Cre mice and then used optogenetics to stimulate HS fibers while performing whole-cell patch clamp recordings from MS/DBB neurons in acute slices. We found that the acetylcholine receptor (AChR) agonist carbachol and the GABAB receptor (GABABR) agonist baclofen significantly decreased HS GABA release in the MS/DBB. Carbachol's effects were blocked by eliminating local GABAergic activity or inhibiting GABABRs, indicating that it was indirectly decreasing HS GABA release by increasing GABAergic tone. There was no effect of acute exposure to amyloid- on HS GABA release. Repetitive stimulation of HS fibers increased spontaneous GABA release in the MS/DBB, revealing that HS projections can modulate local GABAergic tone. These results show that HS GABA release has far-reaching impacts on overall levels of inhibition in the MS/DBB and is under regulatory control by cholinergic and GABAergic activity. This bidirectional modulation of GABA release from local and HS projections in the MS/DBB will likely have profound impact not only on activity within the MS/DBB, but also on output to the hippocampus and hippocampal-dependent learning and memory.