Open Access

Liubov S. Kalinichenko, Mona Krenbauer, Janosh Isert, Marlon Kamlah, Thorben Tanzer, Hannes Rödel, Tobias Müller, Anil Annamneedi, Enes Yağız Akdaş, Volker Eulenburg, Bernd Lenz, Eckart D. Gundelfinger, Johannes Kornhuber, Anna Fejtova, Christian P. Müller

• Background and purpose: Alcohol abuse and affective disorders are severe comorbid psychiatric diseases characterized by impaired brain synaptic transmission. The role of presynaptic scaffolding proteins coordinating presynaptic plasticity and neurotransmitter release, such as Bassoon (Bsn), in the pathogenesis of these disorders remains elusive. Considering the key roles of the dopaminergic and glutamatergic systems in the pathogenesis of affective disorders and alcohol use disorder, we investigated the role of Bsn in these neuronal systems in the regulation of disease-related behaviours. Experimental approach: We employed two mouse models conditionally lacking Bsn in glutamatergic neurons of the forebrain or in dopaminergic neurons. Depression- and anxiety-like and alcohol-related behaviour was evaluated using a battery of behavioural tests in a sex-specific way. Brain monoamine levels were evaluated in several brain regions of mice with Bsn deletion in dopaminergic neurons. KeyBackground and purpose: Alcohol abuse and affective disorders are severe comorbid psychiatric diseases characterized by impaired brain synaptic transmission. The role of presynaptic scaffolding proteins coordinating presynaptic plasticity and neurotransmitter release, such as Bassoon (Bsn), in the pathogenesis of these disorders remains elusive. Considering the key roles of the dopaminergic and glutamatergic systems in the pathogenesis of affective disorders and alcohol use disorder, we investigated the role of Bsn in these neuronal systems in the regulation of disease-related behaviours. Experimental approach: We employed two mouse models conditionally lacking Bsn in glutamatergic neurons of the forebrain or in dopaminergic neurons. Depression- and anxiety-like and alcohol-related behaviour was evaluated using a battery of behavioural tests in a sex-specific way. Brain monoamine levels were evaluated in several brain regions of mice with Bsn deletion in dopaminergic neurons. Key results: Bsn deletion in forebrain glutamatergic neurons reduced alcohol consumption and preserved affective state in male mice. In females, loss of Bsn in these neurons. enhanced anxiety-like behaviour. A Bsn knockout in dopaminergic neurons of males was associated with increased alcohol consumption and anxiety, while depression-like behaviour was attenuated. Females with Bsn deletion in dopaminergic neurons showed no alterations in affective state and alcohol drinking behaviour, but increased dopamine levels in amygdala, indicating a potentially compensatory mechanism. Conclusion and implications: Our findings suggest that Bsn is a sex-specific regulator of affective state and alcohol consumption behaviour in a neuron type-specific way. Bsn exerts dissociating behavioural effects depending on its action in glutamatergic versus dopaminergic neurons.…