Search

The dorsolateral striatum (DLS) of the basal ganglia plays a critical role in action selection and motor control. The DLS receives cortical and thalamic afferents, which are extensively modulated by monoaminergic inputs, such as dopamine and serotonin (5-HT). Dopamine and 5-HT act as circuit neuromodulators by activating both stimulatory (Gs) and inhibitory (Gi) protein-coupled receptors that regulate synaptic mechanisms of plasticity. On a system level, 5-HT signal has been classically associated with learning of negative events, acting as an opponent of dopamine regulation of rewarding processes. Recent evidence has challenged this view, suggesting that 5HT signaling can synergize with dopamine signaling to shape reward-guided behavior. However, the molecular and synaptic correlates of this behavioral role of 5-HT at striatal circuits remain to be established. To address this hypothesis, we investigated the role of serotonergic signaling in regulating the strength of glutamatergic synaptic connections to the Medium Spiny Neurons of the direct pathway (dMSNs), which mediate movement, reward and reinforcement. Specifically, we focused on the regulation of distinct forms of long-term synaptic plasticity that depend on both the relative timing of a neuron output and an input spike (Spike timing-dependent plasticity, STDP), and on the pattern of neuronal stimulation (high-frequency stimulation, HFS). Upon a STDP protocol, the chemo-genetic inhibition of 5-HT release resulted in a long lasting depression (STDP-LTD) of glutamatergic afferents to the dMSNs of the DLS. The synaptic effects of chemo-genetic inhibition of 5-HT release were recapitulated by the pharmacological inhibition of the Gs-coupled 5-HT4 receptor subtype (5-HT4R). This form of LTD was independent from presynaptic CB1 receptor (CB1R) activation, it showed a postsynaptic locus of expression, and it was associated with an increased dendritic Ca2+ signal. We obtained similar results upon HFS; antagonism of 5-HT4R resulted in a CB1R independent form of HFS-LTD, which was associated with enhanced dendritic Ca2+ levels. Collectively, these data provide molecular and synaptic insights on the neuromodulatory role of 5-HT at striatal circuits. Dysfunctional serotonergic modulation of striatal circuits has been associated with repetitive behaviors in obsessive-compulsive disorders (OCD). Thus, elucidating how 5-HT4R manipulation affects aspects of reward-guided behavior, and how this is causally relevant for defined cognitive processes implicated in action control, could facilitate the development of new pharmacological approaches to treat OCD symptoms.

Abnormal hippocampal neural plasticity has been implicated in behavioural abnormalities and complex neuropsychiatric conditions, including bipolar disorder (BD). However, the determinants of this neural alteration remain unknown. This work tests the hypothesis that the neurotransmitter serotonin (5-HT) is a key determinant of hippocampal neuroplasticity, and its absence leads to maladaptive behaviour relevant for BD. Depletion of brain 5-HT in Tph2 mutant mice resulted in reduced behavioural despair, reduced anxiety, marked aggression and lower habituation in novel environments, reminiscent of bipolar-associated manic behaviour. Treatment with valproate produced a substantial improvement of the mania-like behavioural phenotypes displayed by Tph2 mutants. Brain-wide fMRI mapping in mutants revealed functional hippocampal hyperactivity in which we also observed dramatically increased neuroplasticity. Importantly, remarkable correspondence between the transcriptomic profile of the Tph2 mutant hippocampus and neurons from bipolar disorder patients was observed. Chronic stress reversed the emotional phenotype and the hippocampal transcriptional landscape of Tph2 mutants. These changes were associated with inappropriate activation of transcriptional adaptive response to stress as assessed by gene set enrichment analyses in the hippocampus of Tph2 mutant mice. These findings delineate 5-HT as a critical determinant in BD associated maladaptive emotional responses and aberrant hippocampal neuroplasticity, and support the use of Tph2−/− mice as a new research tool for mechanistic and therapeutic research in bipolar disorder.