Fibrosis is a hallmark of atrial structural remodelling closely associated with ageing and atrial fibrillation (AF), however, its underlying molecular mechanisms are incompletely understood. A pathway that is potentially involved in regulating the pathogenesis of AF is the mitogen activated protein kinase cascade (MAPK), since components of the MAPK pathway have been shown to be down-regulated in patients with permanent atrial fibrillation (Kartmann et al. 2005). The MAPK pathway is involved in the regulation of fibrosis in the ventricle in aged/hypertrophied hearts (Lui W et al. 2011; Kyoi S et al. 2006) and fibrosis is linked to atrial fibrillation. To establish the role of the MAPK pathway in atrial function in age, we have developed a conditional knockout mouse model where a central component of this pathway; MKK4, has been specifically deleted from the atria (ACKO) (De Lange F et al. 2003; Liu W et al. 2009). Activity of MKK4 and its downstream effectors and associated changes in electrical, structural and intracellular signalling pathways and physiological consequences in the atrium will be investigated at cellular, tissue- and whole-heart and organism levels. Hearts were assessed for atrial arrhythmia, both in vivo and ex vivo at 3 and 12 months of age (n≥6 per group) and tissue was collected for molecular analysis. In vivo ECG analysis was carried out on mice anesthetized with isoflurane (2.5%) at 3 months of age showed abnormal atrial excitation with reduced P amplitudes (control 0.084mV ± 0.01 vs. ACKO 0.058mV± 0.01 t-test p< 0.05; mean ± SEM) but no arrhythmia; however as the mice aged they became more susceptible to atrial arrhythmia, such as atrial tachycardia (AT) and atrial ectopic beats. Ex vivo hearts from 12 month old MKK4 ACKO mice were more likely to develop AF/AT with electrical programme stimulation than old control mice (37% control mice vs. 100% ACKO mice). Conduction mapping revealed longer atrial conduction times in these mice, which could make the hearts more vulnerable to re-entry arrhythmias. In old ACKO mice an increase in fibrosis was detected by picro-sirius red stain of tissue sections (2.8% ± 0.2 in control vs. 6.1% ± 0.4 in ACKO t-test p<0.01; mean ±SEM). The expression of fibrotic pathway components was assessed using real-time PCR and western blot analysis and ACKO mice had altered patterns of expression of TGF-β1, TGF-β receptors 1 and 2, MMP2/9 and TIMP2, compared to control mice. Development of an atrial specific MKK4 knockout mouse therefore reveals a role for the MAPK pathway in protecting against atrial arrhythmia in age through regulation of fibrotic processes and provides insight into the design of more targeted therapies for atrial fibrillation. The animal studies were performed in accordance with the Home Office and institutional guidelines.