Increased Dendritic Spine Density and Tau Expression Are Associated with Individual Differences in Steroidal Regulation of Male Sexual Behavior

Abstract

Male sexual behavior (MSB) is modulated by gonadal steroids, yet this relationship is highly variable across species and between individuals. A significant percentage (∼30%) of B6D2F1 hybrid male mice demonstrate MSB after long-term orchidectomy (herein after referred to as “maters”), providing an opportunity to examine the mechanisms that underlie individual differences in steroidal regulation of MSB. Use of gene expression arrays comparing maters and non-maters has provided a first pass look at the genetic underpinnings of steroid-independent MSB. Surprisingly, of the ∼500 genes in the medial preoptic area (MPOA) that differed between maters and non-maters, no steroid hormone or receptor genes were differentially expressed between the two groups. Interestingly, best known for their association with Alzheimer’s disease, amyloid precursor protein (APP) and the microtubule-associated protein tau (MAPT) were elevated in maters. Increased levels of their protein products (APP and tau) in their non-pathological states have been implicated in cell survival, neuroprotection, and supporting synaptic integrity. Here we tested transgenic mice that overexpress tau and found facilitated mounting and intromission behavior after long-term orchidectomy relative to littermate controls. In addition, levels of synaptophysin and spinophilin, proteins generally enriched in synapses and dendritic spines respectively, were elevated in the MPOA of maters. Dendritic morphology was also assessed in Golgi-impregnated brains of orchidectomized B6D2F1 males, and hybrid maters exhibited greater dendritic spine density in MPOA neurons. In sum, we show for the first time that retention of MSB in the absence of steroids is correlated with morphological differences in neurons.

Inheritance of steroid-independent male sexual behavior in male offspring of B6D2F1 mice

“…Because previous studies determined that increased APP, tau, and synaptophysin expression levels in the MPOA of B6D2F1 hybrid male mice were associated with steroid-independent male sexual behavior, we analyzed levels of these proteins in not only the B6D2F1 maters and non-maters, but their male offspring as well (Bharadwaj et al, 2013; Park et al, 2010). In concordance with previously reported results, Western blots of APP, tau, and synaptophysin from MPOA tissues showed that all three proteins were significantly higher in B6D2F1 maters relative to those in B6D2F1 non-maters [(p<0.05 for all comparisons; Figure 2A–C; APP: F-value ( 1,8 ) = 7.034, p < 0.05, η 2 =0.88; tau: F-value ( 1,8 ) = 8.476, p < 0.05, η 2 =0.94; synaptophysin: F-value ( 1,8 ) = 5.764, p < 0.05, η 2 =0.72].…”

“…We now have a list of candidate genes that are differentially expressed in the MPOA that correlate with steroid-independent male sexual behavior, and this list is essential towards identifying the chromosomal loci allelic distribution pattern for steroid-independent male sexual behavior (Bharadwaj et al, 2013; Park et al, 2010). It would be of interest to determine in future studies whether the BXB 1 maters also demonstrate a similar pattern of gene expression in the MPOA that correlates with steroid-independent male sexual behavior, as it would provide further evidence for the heritability of this behavioral phenotype.…”

“…Although the exact mechanism by which these proteins regulate steroid-independent male sexual behavior has yet to be determined, recent findings demonstrating a strong association between increased complexity in dendritic architecture in the MPOA with steroid-independent male sexual behavior may provide some insight (Bharadwaj et al, 2013). Synaptophysin may play a significant role in the regulation of synaptic plasticity [(Kwon and Chapman, 2011); reviewed in (Evans and Cousin, 2005)], and recent studies investigating the function of APP and tau have revealed an association with promoting spine formation and proper spine development: (1) in rodents, APP expression peaks around the second postnatal week, during robust synaptogenesis (Loffler and Huber, 1992); (2) increased expression of APP promotes synapse differentiation, synaptogenesis, and increased spine number (Ashley et al, 2005; Lee et al, 2010; Loffler and Huber, 1992; Neve et al, 2000; Qiu et al, 1995; Torroja et al, 1999; Wang et al, 2005; Wang et al, 2009); and (3) small interfering RNA (siRNA) against APP caused impaired synaptic activity in vivo (Herard et al, 2006).…”

“…However, because the results of our study did not demonstrate a direct functional relationship between increased levels of these proteins and increased steroid-independent male sex behavior, we cannot rule out the possibility that increased levels of these proteins are a result of increased steroid-independent male sexual behavior or that the two are both downstream of another factor regulating steroid independent male sexual behavior. However, transgenic mice that overexpress either APP or tau have demonstrated facilitated steroid-independent male sexual behavior, suggesting a causal relationship (Bharadwaj et al, 2013; Park et al, 2010). Further experiments investigating steroid-independent male sexual behavior in conditional overexpressors or knockouts of candidate genes would directly probe whether the relationship is more than correlational.…”

“…Expression of these genes and proteins were significantly higher in maters relative to the non-maters (Park et al, 2010). Furthermore, transgenic male mice that overexpressed either APP or tau, the two proteins products of App and Mapt , respectively, displayed enhanced sexual behavior after orchidectomy compared to control wildtype littermates, demonstrating that the relationship of APP and tau with male sexual behavior were both beyond correlational (Bharadwaj et al, 2013; Park et al, 2010). Because the normal function of both genes have been associated with synaptic plasticity, this led to an investigation that revealed that relative to B6D2F1 non-maters, the maters exhibited higher levels of synaptophysin, a protein generally enriched in synapses and associated with synaptic connectivity ( synaptophysin gene located on the X chromosome) (Bharadwaj et al, 2013).…”