Dynamic changes in extracellular release of GABA and glutamate in the lateral septum during social play behavior in juvenile rats: Implications for sex-specific regulation of social play behavior.

Social play is a motivated and rewarding behavior that is displayed by nearly all mammals and peaks in the juvenile period. Moreover, social play is essential for the development of social skills and is impaired in social disorders like autism. We recently showed that the lateral septum (LS) is involved in the regulation of social play behavior in juvenile male and female rats. The LS is largely modulated by GABA and glutamate neurotransmission, but their role in social play behavior is unknown. Here, we determined whether social play behavior is associated with changes in the extracellular release of GABA and glutamate in the LS and to what extent such changes modulate social play behavior in male and female juvenile rats. Using intracerebral microdialysis in freely behaving rats, we found no sex difference in extracellular GABA concentrations, but extracellular glutamate concentrations are higher in males than in females under baseline conditions and during social play. This resulted in a higher glutamate/GABA concentration ratio in males vs. females and thus, an excitatory predominance in the LS of males. Furthermore, social play behavior in both sexes is associated with significant increases in extracellular release of GABA and glutamate in the LS. Pharmacological blockade of GABA-A receptors in the LS with bicuculline (100 ng/0.5 µl, 250 ng/0.5 µl) dose-dependently decreased the duration of social play behavior in both sexes. In contrast, pharmacological blockade of ionotropic glutamate receptors (NMDA and AMPA/kainate receptors) in the LS with AP-5+CNQX (2mM+0.4mM/0.5 µl, 30 mM+3mM/0.5 µl) dose-dependently decreased the duration of social play behavior in females, but did not alter social play behavior in males. Together, these data suggest a role for GABA neurotransmission in the LS in the regulation of juvenile social play behavior in both sexes, while glutamate neurotransmission in the LS is involved in the sex-specific regulation of juvenile social play behavior.

Vasopressin regulates social recognition in juvenile and adult rats of both sexes, but in sex- and age-specific ways.

In adult male rats, vasopressin (AVP) facilitates social recognition via activation of V1a receptors within the lateral septum. Much less is known about how AVP affects social recognition in adult females or in juvenile animals of either sex. We found that administration of the specific V1a receptor antagonist d(CH(2))(5)[Tyr(Me)(2)]AVP into the lateral septum of adult rats impaired, whereas AVP extended, social discrimination in both sexes. In juveniles, however, we detected a sex difference, such that males but not females showed social discrimination. Interestingly, administration of the V1a receptor antagonist to juveniles (either intracerebroventricularly or locally in the lateral septum) did not prevent social discrimination, but instead significantly decreased the investigation of a novel as opposed to a familiar animal in both sexes, with stronger effects in males. V1a receptors were found to be abundantly expressed in the lateral septum with higher binding density in females than in males. These findings demonstrate that activation of V1a receptors in the lateral septum is important for social recognition in both sexes, and that the roles of septal V1a receptors in social recognition change during development.

Maternal separation interferes with developmental changes in brain vasopressin and oxytocin receptor binding in male rats.

Brain vasopressin V(1A) receptors (V(1A)-R) and oxytocin receptors (OT-R) are important modulators of social behaviors. We recently showed that exposure to maternal separation (MS; 3 h daily, postnatal days 1-14) induces changes in social behaviors in juvenile and adult male rats. Here, we hypothesize that MS induces brain region-specific changes in V(1A)-R and OT-R across development, which in turn, may underlie MS-induced changes in social behaviors. We examined the effects of MS on V(1A)-R and OT-R binding in forebrain regions of juvenile (5 weeks), adolescent (8 weeks), and adult (16 weeks) male rats. Robust age-related changes were found for V(1A)-R and OT-R binding in several brain regions. For example, in the lateral septum V(1A)-R binding increased while OT-R binding decreased with age. Most notably, OT-R binding in the caudate putamen showed a 2-fold decrease while OT-R binding in the ventromedial hypothalamus showed a 4-fold increase with age. Importantly, exposure to MS interfered with these developmental changes in several brain regions. Specifically, MS significantly increased V(1A)-R binding in the piriform cortex (at adolescent and adult ages), the lateral septum (at juvenile age), the hypothalamic attack area (at adolescent age), and the dentate gyrus of the hippocampus (at adolescent age), and decreased V(1A)-R binding in the arcuate nucleus (at juvenile age). Moreover, OT-R binding was significantly lower in the agranular cortex (at juvenile and adolescent age), the lateral septum (at adult age) and the caudate putamen (at adult age), but higher in the medial preoptic area (at adolescent age) and ventromedial hypothalamus (at adult age) after exposure to MS. In conclusion, age-dependent changes in V(1A)-R and OT-R binding are likely associated with the maturation of behaviors, such as sexual and aggressive behaviors, while disruption of these changes by MS might contribute to previously observed changes in social behaviors after MS.

Insulin-like growth factor system in serum and cerebrospinal fluid in patients with multiple sclerosis.

The insulin-like growth factor (IGF) system influences oligodendrocyte survival, myelination, and immune functions. We examined whether alterations in the circulating IGF system occur in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system. We measured concentrations of IGF-I, IGF-II, and insulin-like growth factor binding proteins -1, -2, and -3 in both serum and cerebrospinal fluid from MS patients and age- and sex-matched controls. IGFBP-1 was not detectable in cerebrospinal fluid. We found no significant differences in any of the other components between patients with MS and controls.