Novel insights into the role of the GABAB receptor in depression and anxiety

The GABAB receptor is a functional heterodimer comprising the GABAB1 and GABAB2 subunits, with the GABAB1 subunit displaying two major isoforms, GABAB(1a) and GABAB(1b). Preclinical findings have strongly implicated the GABAB receptor in stress-related psychiatric disorders, however, the precise contribution of the GABAB receptor in depression and anxiety disorders remains unknown. Emerging data suggest that the interaction between adverse environmental conditions, such as early life stress, and a specific genetic composition can increase the risk to develop psychiatric disorders in adulthood. This thesis investigated the role of the GABAB receptor alone or in combination with early-life stress (maternal separation), in modulating antidepressant like and anxiety-related behaviours. Pharmacological blockade of the GABAB receptor with CGP52432 had antidepressant-like behavioural effects. Moreover, mice lacking the GABAB(1b) receptor subunit isoform exhibited antidepressant-like behaviours in adulthood but anxiety-like behaviour in early-life. In response to maternal separation, GABAB(1a)-/- mice exhibited early-life stress-induced anhedonia, a core symptom of depression, while GABAB(1b)-/- mice exhibited a more resilient phenotype. Moreover, when compared with wildtype or GABAB(1a)-/- mice, GABAB(1b)-/- mice that underwent maternal separation exhibited enhanced stressinduced neuronal activation in the hippocampus and in the nucleus accumbens (NAcc), a critical area for anhedonia thus suggesting that enhanced stress-induced neuronal activation in the hippocampus and NAcc in GABAB(1b)-/- mice may be important for their antidepressant-like phenotype and their resilience to stress-induced anhedonia. Pharmacological blockade of GABAB receptor and GABAB(1b) receptor subunit isoform loss of function increased adult hippocampal cell proliferation, thus suggesting that increased hippocampal neurogenesis could be a potential mechanism for the antidepressant-like effects of GABAB receptor antagonists and GABAB(1b) receptor subunit isoform disruption. Finally, this thesis investigated whether the expression of several genes involved in hippocampal neurogenesis or the antidepressant response were altered in the mouse hippocampus following chronic treatment with a GABAB receptor antagonist.

Corporeal prisons: dynamics of body and mise-en-scène in three films by Paul Schrader

This thesis focuses on the complex relationship between representations of the human body and the formal processes of mise-en-scène in three consecutive films by the writer-director Paul Schrader: American Gigolo (1980), Cat People (1982) and Mishima: A Life in Four Chapters (1985). While Schrader’s work has typically been critiqued under the broad category of masculinity in crisis (and often as a subset of the films of his more famous long-time collaborator, Martin Scorsese), I focus on a fiveyear early period of his filmography when he sought to explore his key themes of bodily crisis, fragmentation and alienation through an unusually intense focus upon the expressive potential of film form, specifically via the combined elements of colour, lighting, camerawork and production design. By approaching these three films as corporeal character studies of troubled figures whose emotional and psychosexual neurosis is experienced in and through the body, I will locate Schrader’s filmmaking process and style within the thematic and aesthetic contexts of both his own early film criticism and the European and Japanese art cinemas that he claims as his primary influence. In doing so, I will establish Schrader’s position as a director whose literary and theological background differentiated him from his peers of the postclassical Hollywood generation, and who thus continually sought to develop his own visual literacy through his relationship with the camera and his collaborations with more overtly style-oriented film artists. But instead of merely focusing on mise-en-scène to gain a formalist appreciation of these films, I mobilise stylistic analysis as a new critical approach towards the problematic discourses of identity and embodiment that have haunted Schrader’s career from the beginning. In particular, I argue that paying closer attention to Schrader’s formal choices sheds new light on how these films – which he approached as exercises in style – repeatedly deal with the volatile and unavoidably body-oriented categories of race, gender and sexuality. In the process, I argue that a formalist attentiveness to mise-en-scène can also provide valuable cultural insights into Schrader’s oeuvre.