In aggregate, these cellular and molecular changes further compromise neuronal function. Tangles in boxers with dementia pugilistica/CTE are structurally and chemically similar to those found in AD, in which CTE tangles also consist of hyperphosphorylated and ubiquitinated tau (Dale et al., 1991; Tokuda et al., 1991). Hyperphosphorylated tau from dementia pugilistica and AD brains is phosphorylated at the same amino acids, including the AT8 epitope, contains all six tau isoforms, and

shows the same relation between 3- and 4-repeat tau (Schmidt et al., 2001) (Figure 2). However, RG-7204 it should be noted that the tangles are found in different populations of cortical pyramidal neurons;

in dementia pugilistica/CTE, tangles are found in the superficial neocortical layers, while tangles in AD are found in deep and in superficial layers (Corsellis et al., 1973; Hof et al., 1992; McKee et al., 2009). Furthermore, tau pathology in CTE is patchy and irregularly distributed, possibly related to the many different directions of shearing forces induced by physical trauma (McKee et al., 2009). Experimental studies in animals suggest that intra-axonal tau accumulation and tau phosphorylation may be consequences of repeated brain trauma. selleck chemical Controlled brain trauma in animal models has been shown to increase tau immunoreactivity and tau phosphorylation in the perinuclear cytoplasm and in elongated

neuritis (Tran et al., 2011). These abnormalities correlate with injury severity (Tran et al., 2011). Studies on brain trauma induced by rotational acceleration in experimental animals show an accumulation of both tau and neurofilament proteins in damaged axons (Smith et al., 1999). Treatment with γ-secretase inhibitors mitigates amyloid pathology but does not affect TBI-induced whatever tangle formation, suggesting that TBI-induced tau pathology is not a downstream event of Aβ accumulation and plaque formation (Tran et al., 2011). The neurochemical disturbances that trigger tau pathology in CTE are not known in detail, but recent studies show that TBI induces an abnormal intra-axonal activation and accumulation in kinases that can phosphorylate tau (Tran et al., 2012). The kinase c-Jun N-terminal kinase (JNK) is markedly activated in damaged axons, and inhibition of JNK activity was found to reduce the accumulation of both total and phosphorylated tau in injured axons (Tran et al., 2012). After identification of Aβ as the key component of plaques in AD, Roberts et al. (1990) re-examined brains from the classic Corsellis report (Corsellis et al., 1973) to determine whether Aβ pathology may also be a key histopathological characteristic in dementia pugilistica.

In this article we refer to both the perinatal and adult cells as NG2-glia. The sheer number of NG2-glia in the adult brain and their uniform distribution in both gray and white matter seemed counterintuitive. Given their presumed role as oligodendrocyte

precursors, should they not be concentrated in white matter where they would presumably be in most demand for myelinating axons? Why should so many precursor cells persist in the mature adult brain in any case? Moreover, the complex process-bearing morphology of NG2-glia in vivo seemed more in keeping with differentiated cells than immature precursors. Perhaps NG2-glia served a dual purpose—as a source of oligodendrocytes during development but fulfilling some more homeostatic or “functional” role in the adult (Nishiyama et al., 1999, Butt et al., ISRIB in vivo 2002, Wigley et al., 2007 and Nishiyama et al., 2009). Anatomical studies revealed that NG2-glia form close contacts with neurons—with axons at nodes of Ranvier and in close proximity to synapses at neuronal cell bodies (Butt et al., 1999, Butt et al., 2002 and Wigley and Butt, 2009).

The hypothesis was born that NG2-glia, or a subset of them, might be involved in some aspects of information processing, in partnership with neurons. This idea took off—and NG2-glia became really “exciting”—when electrophysiologists weighed in. It was already known that NG2-glia express some ion channels and neurotransmitter receptors and that glutamate can influence their proliferation and differentiation in culture http://www.selleckchem.com/products/abt-199.html (Barres et al., 1990, Patneau et al., 1994 and Gallo et al., 1996). However, the first demonstration that NG2-glia in the hippocampus receive long-range synaptic input from neurons in vivo sent waves through the research community (Bergles et al., 2000). Synaptic communication between neurons and NG2-glia, both glutamatergic and GABAergic, was subsequently demonstrated in the cerebellum and cerebral cortex, both in gray and white matter (Lin and Bergles, 2002, Chittajallu et al., 2004, Káradóttir et al., 2005, Lin et al., 2005, Salter and Fern, 2005, Paukert and Bergles,

2006, Kukley et al., 2007, Ziskin et al., 2007 and Hamilton et al., 2009). Physical synapses were identified between NG2 glia and unmyelinated axons in the corpus Ketanserin callosum (Kukley et al., 2007 and Ziskin et al., 2007). Some NG2-glia were found to display spiking sodium currents in response to an initial depolarization (Chittajallu et al., 2004, Káradóttir et al., 2008, Mangin et al., 2008 and De Biase et al., 2010). Suddenly, NG2-glia appeared exotic, ambiguous—glial in form (since they do not possess axons) but with some electrical properties akin to neurons. Their chimeric nature also contributed to the idea that NG2-glia, in their “other” role as precursor cells, might be more malleable than previously imagined and perhaps capable of transforming into neurons as well as glia. One study in particular launched the idea of NG2-glia as latent neural stem cells.

5% baseline amplitude (p < 0.05 versus nonconditioned) (Figure 4A–4Bi). Next we blocked tPA activity to determine if extracellular cleavage of proBDNF to mBDNF was required for the visually induced facilitation. Bath application of the

inhibitor tPA-stop blocked LTP induction (80% ± 7.1%, p < 0.01 versus conditioned) (Figure 4Bii). As tPA can be involved in cascades other than the cleavage of proBDNF, we tested LTP induction in tectal cells in which BDNF expression had been knocked down by BDNF MO electroporation. Knockdown of BDNF prevented the facilitation induced by conditioning (125% ± 5.3%, p < 0.05 versus conditioned; Figure 4Biii). In contrast, electroporation of a control scrambled MEK inhibitor MO (n = 3) did not interfere with facilitation of LTP by visual conditioning, resulting in selleck compound a potentiation that was indistinguishable from that observed in untreated, conditioned animals (n = 6). These groups were therefore combined. These findings imply that proBDNF synthesized in response to visual conditioning may be cleaved in a tPA-dependent manner in response to the LTP protocol, and that the resulting production of mBDNF facilitates LTP. Activation of the TrkB receptor tyrosine kinase is the main pathway by which mBDNF

initiates downstream signaling. Inhibition of TrkB signaling with the receptor tyrosine kinase inhibitor K252a entirely blocked LTP induction in conditioned animals (97% ± 3.8%, p < 0.05 versus no drug; Figure 4iv) in agreement with previous reports (Du et al., 2009 and Mu and Poo, 2006). Together, our findings demonstrate that the BDNF synthesized in response to 20 min of robust visual Histamine H2 receptor conditioning, can facilitate bidirectional plasticity at the retinotectal synapse hours later. As developmental circuit refinement is thought to rely upon environmentally driven strengthening of appropriate, and weakening of inappropriate, synapses through mechanisms like LTP and LTD (Katz and Shatz, 1996 and Zhang and Poo, 2001), we next tested whether visual conditioning might facilitate the ongoing process of circuit refinement. Visual acuity

is a measure of the ability to resolve spatial details. One method for measuring acuity in humans is the Teller acuity test (Dobson and Teller, 1978), in which preverbal infants will preferentially look at a grating that they can resolve, compared to either a gray screen of comparable luminance or a higher spatial frequency grating that they cannot resolve. Furthermore, cortical responses to gratings of different sizes determined by measuring transcranial visually evoked potentials can be extrapolated to determine a subject’s acuity thresholds, with comparable results to the behavioral tests (Campbell and Maffei, 1970 and Good, 2001). To determine if proBDNF produced by visual conditioning participates in the ongoing process of circuit refinement, we subjected tadpoles to visual conditioning and then returned them to their normal rearing environment for 7–11 hr.