Lly, in light of the cholinergic hippocampal and frontal cortex neuroplasticity data and their association with better cognitive performance, the former seems more likely. Taken together, the cholinergic and glutamatergic findings showing an upregulation of neurotransmitter systems lends support to the suggestion that the hippocampal and cortical synapses are indeed more active during MCI than in AD (Goekoop et al., 2006). To this end, the cortical glutamatergic system needs to be more fully investigated in the hippocampus during the onset of AD particularly in the context of therapeutics. In this regard, the use of memantine, an uncompetitive NMDA receptor antagonist and a FDA-approved treatment for moderate to severe AD has been challenged (Reisberg et al., 2006; Danysz and Parsons, 2012).Author Manuscript Author Manuscript Author Manuscript Author ManuscriptNeuroscience. Author manuscript; available in PMC 2016 September 12.Mufson et al.PageAn unanswered question is why select cholinergic basal forebrain (CBF) neuron subfields respond with a neuroplastic response and others do not in MCI. In this regard, the number of medial septal/diagonal band cholinergic neurons, which are mainly hippocampal projecting, is relatively spared compared to neurons in other CBF nuclei in AD (Mufson et al., 1989; Vogels et al., 1990) in AD and this region does not lose volume in MCI compared to controls (George et al., 2011; Kilimann et al., 2014). The lack of significant degenerative changes in this region may explain its ability to sprout new cholinergic terminals into the denervated hippocampus in response to entorhinal cortex disconnection. In a similar vein, the upregulation of ChAT LitronesibMedChemExpress LY-2523355 C.I. 75535 custom synthesis activity in the frontal cortex may be related to the observation that anterior medial cholinergic neurons located within the substantia innominata, which innervate the frontal cortex (Mesulam et al., 1983; Bierer et al., 1995), are less vulnerable to neuronal degeneration relative to other cholinergic nucleus basalis subfields in AD (Mufson et al., 1989). These CBF neurons are affected to a greater degree than the hippocampalprojecting septal cholinergic neurons in AD (Mufson et al., 1989; Vogels et al., 1990). Maintenance of the neuronal cholinergic phenotype may, at least in part, explain the ability of these neurons to reinnervate the denervated hippocampus and account for the upregulation of ChAT activity in this region early in the disease (DeKosky et al., 2002). The ability to generate new cholinergic profiles is in contrast to that seen in the MCI frontal cortex where despite an upregulation of ChAT activity there is no net increase in cholinergic fibers and varicosities in MCI (Ikonomovic et al., 2007). These studies demonstrate that a biochemical up-regulation of ChAT in MCI frontal cortex does not reflect regional structural reorganization of cholinergic fibers. However, it likely activity compensates for the decrease in cholinergic fiber/axon varicosities found in the AD frontal cortex. Together, these data suggest that two different processes that result in similar chemoplastic responses drive the upregulation of cholinergic activity seen in the MCI hippocampus and frontal cortex. In either case the “drive” for cholinergic reinnervation is strong.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptHippocampal Plasticity and Neurotrophins in MCI and ADThe neurotrophin, Nerve Growth Factor (NGF) is a product of a single gene located on chrom.Lly, in light of the cholinergic hippocampal and frontal cortex neuroplasticity data and their association with better cognitive performance, the former seems more likely. Taken together, the cholinergic and glutamatergic findings showing an upregulation of neurotransmitter systems lends support to the suggestion that the hippocampal and cortical synapses are indeed more active during MCI than in AD (Goekoop et al., 2006). To this end, the cortical glutamatergic system needs to be more fully investigated in the hippocampus during the onset of AD particularly in the context of therapeutics. In this regard, the use of memantine, an uncompetitive NMDA receptor antagonist and a FDA-approved treatment for moderate to severe AD has been challenged (Reisberg et al., 2006; Danysz and Parsons, 2012).Author Manuscript Author Manuscript Author Manuscript Author ManuscriptNeuroscience. Author manuscript; available in PMC 2016 September 12.Mufson et al.PageAn unanswered question is why select cholinergic basal forebrain (CBF) neuron subfields respond with a neuroplastic response and others do not in MCI. In this regard, the number of medial septal/diagonal band cholinergic neurons, which are mainly hippocampal projecting, is relatively spared compared to neurons in other CBF nuclei in AD (Mufson et al., 1989; Vogels et al., 1990) in AD and this region does not lose volume in MCI compared to controls (George et al., 2011; Kilimann et al., 2014). The lack of significant degenerative changes in this region may explain its ability to sprout new cholinergic terminals into the denervated hippocampus in response to entorhinal cortex disconnection. In a similar vein, the upregulation of ChAT activity in the frontal cortex may be related to the observation that anterior medial cholinergic neurons located within the substantia innominata, which innervate the frontal cortex (Mesulam et al., 1983; Bierer et al., 1995), are less vulnerable to neuronal degeneration relative to other cholinergic nucleus basalis subfields in AD (Mufson et al., 1989). These CBF neurons are affected to a greater degree than the hippocampalprojecting septal cholinergic neurons in AD (Mufson et al., 1989; Vogels et al., 1990). Maintenance of the neuronal cholinergic phenotype may, at least in part, explain the ability of these neurons to reinnervate the denervated hippocampus and account for the upregulation of ChAT activity in this region early in the disease (DeKosky et al., 2002). The ability to generate new cholinergic profiles is in contrast to that seen in the MCI frontal cortex where despite an upregulation of ChAT activity there is no net increase in cholinergic fibers and varicosities in MCI (Ikonomovic et al., 2007). These studies demonstrate that a biochemical up-regulation of ChAT in MCI frontal cortex does not reflect regional structural reorganization of cholinergic fibers. However, it likely activity compensates for the decrease in cholinergic fiber/axon varicosities found in the AD frontal cortex. Together, these data suggest that two different processes that result in similar chemoplastic responses drive the upregulation of cholinergic activity seen in the MCI hippocampus and frontal cortex. In either case the “drive” for cholinergic reinnervation is strong.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptHippocampal Plasticity and Neurotrophins in MCI and ADThe neurotrophin, Nerve Growth Factor (NGF) is a product of a single gene located on chrom.