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hippocampal neurons, ranging from modulation of synaptic transmission and plasticity to
structural changes of dendrites, spines, and presynaptic terminals [McAllister et al., 1999;
Poo, 2001; Tyler et al., 2002; Lu, 2003; Amaral et al., 2007]. Conversely, brief (<300
milliseconds) and highly targeted (<20 μm) BDNF pulses evoke fast Na + currents through
direct activation of Na v 1.9 channels [Blum et al., 2002] and slower non-selective cationic
currents mediated by transient receptor potential canonical subfamily 3 (TRPC3) channels [Li
et al., 1999]. A recent study shows that BDNF elicits a nonselective cationic current ( I BDNF ) in
hippocampal CA1 pyramidal neurons that requires functional Trk receptors, phospholipcase
C activity, IP 3 receptors, full intracellular Ca 2+ stores, and extracellular Ca 2+ , suggesting the
involvement of TRPC channels [Amaral and Pozzo-Miller, 2007]. I BDNF was absent in
neurons loaded with anti-TRPC3 function-blocking antibodies or in those transfected with a
siRNA construct designed to knockdown TRPC3 expression. BDNF also increased the levels
of surface accessible TRPC3 in cultured hippocampal neurons with a requirement for PI3K
and a time-course that paralleled the activation of I BDNF , which was also blocked by a PI3K
inhibitor [Amaral and Pozzo-Miller, 2007]. Moreover, siRNA-mediated TRPC3 channel
knockdown prevented the BDNF-induced increase of dendritic spine density in CA1
pyramidal neurons. TRPC channels may represent novel mediators of BDNF-initiated
dendritic remodeling through the activation of a slowly developing and sustained membrane
depolarization [Amaral and Pozzo-Miller, 2007].
Neurons of the medial septum and diagonal band of Broca (MS-DBB) project to the
hippocampus, modulating its activity and providing important input for cognitive functions
such as memory [Winson, 1978]. In addition to cholinergic and GABAergic neurons,
glutamatergic neurons [Colom et al., 2005] and neurons that can release acetylcholine and
glutamate simultaneously [Allen et al., 2006] have recently been described in the basal
forebrain. It is well known that NGF promotes synaptic function of cholinergic basal
forebrain neurons [Hartikka and Hefti, 1988], and new findings indicate that NGF is capable
of increasing both acetylcholine and glutamate transmission from cholinergic MS-DBB
neurons [Huh et al., 2008]. Intriguingly, the latter actions of NGF were mediated by its
receptor p75 NTR , and not TrkA. Accumulating evidence suggests that dysfunctional NGF
signaling is implicated in AD. Individuals with early to late stages of AD display reductions
in TrkA and p75NTR expression that are correlated with their performance on memory tests
[Salehi et al., 2003]. In addition, NGF replacement therapy has emerged as a potential
treatment for AD. In a recent phase I clinical trial, implanting NGF-producing fibroblasts into
the basal forebrain of AD patients significantly slowed the rate of cognitive decline and
increased cortical glucose uptake [Tuszynski et al., 2005]. Conceivably, dysfunctional NGF
signaling in AD may cause reductions in both acetylcholine and glutamate release from septal
cholinergic neurons, and both changes may contribute to the cognitive deficits associated with
AD. Conversely, increasing NGF levels in the brain may enhance both cholinergic and
glutamatergic transmission in the septo hippocampal circuit, improving cognitive functions.
Brain development and function depend on glial cells, as they guide the migration of
neuronal somata and axons [Silver et al., 1982; Kuwada, 1986; Rakic, 1990], promote the
survival and differentiation of neurons [Hosoya et al., 1995; Jones et al., 1995; Pfrieger and
Barres, 1995], and insulate and nourish neurons [Tsacopoulos and Magistretti, 1996]. Glial
processes ensheath most synapses in the brain [Pomeroy and Purves, 1988; Peters et al.,
1991], and a number of studies now support the notion that glial cells do indeed promote the
formation and function of synapses. For example, retinal ganglion cells in vitro formed
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