Multiple de novo variants in the PCLO gene, including two loss-of-function (LoF) variants and two potentially damaging missense variants, have been identified in ASD probands from the Autism Sequencing Consortium, the SPARK cohort, and the MSSNG cohort (Satterstrom et al., 2020; Zhou et al., 2022). A meta-analysis of genetic data from two schizophrenia cohorts combined with whole-exome sequencing data from the Autism Sequencing Consortium in Liu et al., 2023 identified PCLO as a shared risk gene for schizophrenia and ASD (P-value 5.8E-08). Both rare and common variants in the PCLO gene have previously been found to associate with schizophrenia, bipolar disorder, and major depressive disorder (Sullivan et al., 2009; Bochdanovits et al., 2009; Choi et al., 2011; Chen et al., 2021).
Molecular Function
The protein encoded by this gene is part of the presynaptic cytoskeletal matrix, which is involved in establishing active synaptic zones and in synaptic vesicle trafficking. An autosomal recessive form of pontocerebellar hypoplasia (PCH3; OMIM 608027) was found to be caused by a homozygous nonsense variant in the PCLO gene in a consanguineous Omani family in which affected individuals also presented with developmental delay and seizures (Ahmed et al., 2015).
Downregulation of Piccolo in the medial prefrontal cortex results in a decrease of regional synaptic proteins, accompanied with electrophysiological impairments, such as decreased paired pulse facilitation and decreased long-term potentiation in the prefrontal cortex. The Piccolo-suppressed mice showed an enhanced locomotor activity in response to novelty, impaired auditory prepulse inhibition, and cognitive dysfunction in novel object recognition, contextual fear conditioning and spontaneous alternation. Hyperlocomotion and sensory behaviors were partially ameliorated by the antipsychotic drug risperidone, but cognitive phenotypes were not rescued. Piccolo-suppressed mice that received mild social defeat stress showed sensitivity in additional testing for social interaction and behavioral despair.
Model Type:
Genetic
Model Genotype:
wildtype
Mutation:
Viral vectors were designed to express an antisense sequence for Pclo and an enhanced GFP sequence (AAV-Pclo miRNA/EGFP vectors) based on murine miR-155 as a backbone under cytomegalovirus promotor. Viral vectors containing only the enhanced GFP sequence (AAV-EGFP vectors) were used as controls. The microinjection of AAV vectors into the medial prefrontal cortex of the mice. The mice were used for experiments four weeks after the AAV-injections.
Allele Type: Knockdown
Strain of Origin: N/A
Genetic Background: C57BL/6J
ES Cell Line: N/A
Mutant ES Cell Line: Model Source: Atsumi Nitta et al. (PMID 34206873)
Description: Piccolo knockdown mice were found to have significantly lower basal levels of extracellular Glutamate in the mPFC and dorsal striatum than controls. Additionally, there was a significant reduction in the depolarization-evoked Glutamate in the mPFC and dorsal striatum of Piccolo knockdown mice. There is also a reduction in the optogenetically induced Glutamate surge in the dorsal striatum.
Description: No marked difference in the basal levels of extracellular GABA was observed in the dorsal striatum of Piccolo knockdown mice compared to control mice. However, there was a significant reduction in the depolarization-evoked dopamine elevation in the dorsal striatum of Piccolo knockdown mice.
Description: Suppression of Piccolo diminishes theta-burst-induced long-term potentiation (LTP) in the mPFC. Repeated theta-burst stimulation was then used to determine the LTP saturation. Control mice have greater LTP after repeated theta-burst stimulation than Piccolo knockdown mice.
Description: No marked difference in the basal levels of extracellular dopamine was observed in the mPFC or dorsal striatum of Piccolo knockdown mice compared to control mice. However, there was a significant reduction in the depolarization-evoked dopamine elevation in the mPFC of Piccolo knockdown mice, and a significant increase in the depolarization-evoked dopamine elevation in the dorsal striatum compared to controls. There is also a reduction in the optogenetically induced Glutamate depression in the dorsal striatum.
Description: Significant impairment in the 78-dB prepulse/120-dB pulse trial was observed in Piccolo knockdown mice compared to control mice when the acoustic startle response and PPI (psychometric measure of sensorimotor gating) were measured.
Description: Social defeat stress-exposed Piccolo knockdown mice show a significantly shorter interaction time in the social interaction test than non-stress-exposed Piccolo knockdown mice. This difference is not present between stressed and non-stressed control mice.
Description: Social defeat stress-exposed Piccolo knockdown mice show a significantly longer immobility time in the forced swim test than non-stress-exposed Piccolo knockdown mice. This difference is not present between stressed and non-stressed control mice.
Description: Control mice show cognitive preference, as indicated by a longer exploration time for the novel object than for a familiar object. However, Piccolo knockdown mice show a significantly shorter exploration time for the novel object than control mice.
Description: Piccolo knockdown mice show a decreased expression of presynaptic protein SNAP-25 in the mPFC, while the Munc18 and Synaptophysin levels remained unchanged.
Exp Paradigm: SNAP-25
Description: The degree of phosphorylation at the CaMKII regulatory site in Synapsin I (Ser603) is lower in Piccolo knockdown mice than in controls.
Exp Paradigm: Phospho-synapsin I
