Conditional knockout of FGFR2 in radial glial cells affects the development of the prefrontal cortex, as well as its projection areas (Stevens et al., 2010). Moreover, short-term learning and neurogenesis in the dentate gyrus are dependent on FGFR2 functioning in the adult hippocampus. Conversely, long-term Crizotinib clinical trial learning and the number of parvalbumin interneurons are dependent on FGFR2 in the embryonic hippocampus (Stevens et al., 2012). Similarly, FGFR3 is predominantly expressed by astrocytes in the brain. FGFR3 knockout mice

exhibit deficits in cortical and hippocampal volumes (Moldrich et al., 2011). These effects appear to be the most extreme on GABAergic neurons of the telencephalon. Moreover, FGFR3 appears to be more important in the formation of the caudal cortex and resultant projections. However, the information on the function of this receptor in the brain is sparse, yet of great interest given its consistent downregulation in human depression (see below). Interestingly, there are additional endogenous molecules that can bind FGF ligands.

One such example is FGF binding protein 3 (FGFBP3), a truncated version of FGFR1 that does not signal but has the ability to bind FGF ligands, likely acting as a local sink toward some ligands (Hanneken et al., 1994). A recent study showed that MEK inhibition inactivation of FGFBP3, by a targeted gene deletion increased anxiety behavior in rodents (Yamanaka et al., 2011). However, the relative affinity of FGFBP3 for the different FGF ligands remains under evaluation. In summary, the predominant receptor subtypes in the rodent and human brain highlight the importance of the hippocampus. Moreover, FGF receptor signaling plays important roles

in neurogenesis, cortical, and hippocampal development, as well as models of learning and memory. Finally, the development of constructs that can bind FGF ligands will present an intriguing mechanism for further regulation of the available pool of active ligands and their ability to exert functional changes in the CNS. It should also be mentioned that other ligands, distinct from the classical FGF molecules, have been shown to bind click here to FGF receptors. One of the best characterized molecules in this class is neural cell adhesion molecule (NCAM) (Christensen et al., 2006; Kiselyov et al., 2005; Williams et al., 1994). Later in this review, we will summarize their role in affective and cognitive behavior. Alterations in the FGF system were first identified in cortical brain regions in individuals with MDD compared to controls (Evans et al., 2004). Moreover, the FGF family was not altered in individuals with bipolar disorder (BPD). Although differences were observed in FGF1, FGF2, FGF9, FGF12, FGFR2, and FGFR3, no differences were seen in FGF7, FGF13, FGF14, or FGFR1 (see Table 1).