Large excitatory synapses with multiple active zones ensure reliable and fast information transfer at specific points in neuronal circuits. However, the mechanisms that determine synapse size in CNS circuits are largely unknown. Here we use the calyx of Held synapse, a major relay in the auditory system, to identify and study signaling pathways that specify large nerve terminal size and fast synaptic transmission. Using genome-wide screening, we identified bone morphogenetic proteins (BMPs) as candidate signaling molecules in the area of calyx synapses. Conditional deletion of BMP receptors in the auditory system of mice led to aberrations of synapse morphology and function specifically at the calyx of Held, with impaired nerve terminal growth, loss of monoinnervation and less mature transmitter release properties. Thus, BMP signaling specifies large and fast-transmitting synapses in the auditory system in a process that shares homologies with, but also extends beyond, retrograde BMP signaling at Drosophila neuromuscular synapses.

The unique anatomical and functional features of principal and interneuron populations are critical for the appropriate function of neuronal circuits. Cell type-specific properties are encoded by selective gene expression programs that shape molecular repertoires and synaptic protein complexes. However, the nature of such programs, particularly for post-transcriptional regulation at the level of alternative splicing is only beginning to emerge. We here demonstrate that transcripts encoding the synaptic adhesion molecules neurexin-1,2,3 are commonly expressed in principal cells and interneurons of the mouse hippocampus but undergo highly differential, cell type-specific alternative splicing. Principal cell-specific neurexin splice isoforms depend on the RNA-binding protein Slm2. By contrast, most parvalbumin-positive (PV+) interneurons lack Slm2, express a different neurexin splice isoform and co-express the corresponding splice isoform-specific neurexin ligand Cbln4. Conditional ablation of Nrxn alternative splice insertions selectively in PV+ cells results in elevated hippocampal network activity and impairment in a learning task. Thus, PV-cell-specific alternative splicing of neurexins is critical for neuronal circuit functionDOI: http://dx.doi.org/10.7554/eLife.22757.001

The cerebellum integrates descending motor commands and sensory information to generate predictions and detect errors during ongoing behaviors. Cerebellar computation has been proposed to control motor but also non-motor behaviors, including reward expectation and cognitive flexibility. However, the organization and functional contribution of cerebellar output channels are incompletely understood. Here, we elaborate the cell-type specificity of a broad connectivity matrix from the deep cerebellar nuclei (DCN) to the dorsal striatum in mice. Cerebello-striatal connections arise from all deep cerebellar subnuclei and are relayed through intralaminar thalamic nuclei (ILN). In the dorsal striatum, these connections target medium spiny neurons, but also ChAT-positive interneurons, a class of tonically active interneurons implicated in shifting and updating behavioral strategies. Chemogenetic silencing of cerebello-striatal connectivity modifies function of striatal ChAT-positive interneurons. We propose that cerebello-striatal connections relay cerebellar computation to striatal circuits for goal-directed behaviors.