Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.

SorCS2 is a member of the Vps10p-domain receptor gene family receptors with critical roles in the control of neuronal viability and function. Several genetic studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. Here we report that hippocampal N-methyl-d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2-deficient mice. This defect was traced to the ability of SorCS2 to form complexes with the neurotrophin receptor p75, required for pro-brain-derived neurotrophic factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine kinase TrkB to elicit long-term potentiation. Although the interaction with p75 was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its translocation to postsynaptic densities for synaptic tagging and maintenance of synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB autophosphorylation, and activation of downstream signaling cascades, impacting neurite outgrowth and spine formation. Accordingly, Sorcs2 mice displayed impaired formation of long-term memory, increased risk taking and stimulus seeking behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our results identify SorCS2 as an indispensable coreceptor for p75 and TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders.

In major depression, one line of research indicates that a dysfunctional GABAergic inhibitory system is linked to the appearance of depressive symptoms. However, as the mechanistic details of such GABAergic deficit are largely unknown, we undertook a functional investigation of the GABAergic system in the rat chronic mild stress model of depression. Adult rats were exposed to an eight-week long stress protocol leading to anhedonic-like behavior. In hippocampal brain slices, phasic, and tonic GABA(A) receptor-mediated currents in dentate gyrus granule cells were examined using patch-clamp recordings. In granule cells, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was reduced to 41% in anhedonic-like rats, which was associated with a reduced probability of evoked GABA release. Using immunohistochemical analysis, there was no change in the number of parvalbumin-positive interneurons in the dentate gyrus. Notably, we observed a 60% increase in THIP-activated tonic GABA(A) mediated current in anhedonic-like rats, suggesting an upregulation of extrasynaptic GABA(A) receptors. Finally, five weeks treatment with the antidepressant escitalopram partially reversed the sIPSCs frequency. In summary, we have revealed a hippocampal dysfunction in the GABAergic system in the chronic mild stress model of depression in rats, caused by a reduction in action potential-dependent GABA release. Since the function of the GABAergic system was improved by antidepressant treatment, in parallel with behavioral read outs, it suggests a role of the GABAergic system in the pathophysiology of depression.

Cysteine string protein-α (CSP-α) is a synaptic vesicle protein that prevents activity-dependent neurodegeneration by poorly understood mechanisms. We have studied the synaptic vesicle cycle at the motor nerve terminals of CSP-α knock-out mice expressing the synaptopHluorin transgene. Mutant nerve terminals fail to sustain prolonged release and the number of vesicles available to be released decreases. Strikingly, the SNARE protein SNAP-25 is dramatically reduced. In addition, endocytosis during the stimulus fails to maintain the size of the recycling synaptic vesicle pool during prolonged stimulation. Upon depolarization, the styryl dye FM 2-10 becomes trapped and poorly releasable. Consistently with the functional results, electron microscopy analysis revealed characteristic features of impaired synaptic vesicle recycling. The unexpected defect in vesicle recycling in CSP-α knock-out mice provides insights into understanding molecular mechanisms of degeneration in motor nerve terminals.

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Autism spectrum disorders (ASDs) comprise a group of clinical phenotypes characterized by repetitive behavior and social and communication deficits. Autism is generally viewed as a neurodevelopmental disorder where insults during embryonic or early postnatal periods result in aberrant wiring and function of neuronal circuits. Neurexins are synaptic proteins associated with autism. Here, we generated transgenic βNrx1ΔC mice in which neurexin function is selectively impaired during late postnatal stages. Whole-cell recordings in cortical neurons show an impairment of glutamatergic synaptic transmission in the βNrx1ΔC mice. Importantly, mutant mice exhibit autism-related symptoms, such as increased self-grooming, deficits in social interactions, and altered interaction for nonsocial olfactory cues. The autistic-like phenotype of βNrx1ΔC mice can be reversed after removing the mutant protein in aged animals. The defects resulting from disruption of neurexin function after the completion of embryonic and early postnatal development suggest that functional impairment of mature circuits can trigger autism-related phenotypes.

Mature BDNF and its precursor proBDNF may both be secreted to exert opposite effects on synaptic plasticity in the hippocampus. However, it is unknown how proBDNF and mature BDNF affect the excitability of GABAergic interneurons and thereby regulate GABAergic inhibition. We made recordings of GABAergic spontaneous IPSCs (sIPSCs) in mouse dentate gyrus granule cells and found that chronic or acute BDNF reductions led to large increases in the sIPSC frequencies, which were TTX (tetrodotoxin) sensitive and therefore action-potential driven. Conversely, addition of mature BDNF, but not proBDNF, within minutes led to a decrease in the sIPSC frequency to 44%. Direct recordings from fast-spiking GABAergic interneurons revealed that mature BDNF reduced their excitability and depressed their action potential firing, whereas proBDNF had no effect. Using the TrkB inhibitor K-252a, or mice deficient for the common neurotrophin receptor p75 NTR , the regulation of GABAergic activity was shown specifically to be mediated by BDNF binding to the neurotrophin receptor TrkB. In agreement, immunohistochemistry demonstrated that TrkB, but not p75 NTR , was expressed in parvalbumin-positive interneurons. Our results suggest that mature BDNF decreases the excitability of GABAergic interneurons via activation of TrkB, while proBDNF does not impact on GABAergic activity. Thus, by affecting the firing of GABAergic interneurons, mature BDNF may play an important role in regulating network oscillations in the hippocampus.

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