Schizophrenia-Like Behavioral Impairments in Mice with Suppressed Expression of Piccolo in the Medial Prefrontal Cortex

Abstract

Piccolo, a presynaptic cytomatrix protein, plays a role in synaptic vesicle trafficking in the presynaptic active zone. Certain single-nucleotide polymorphisms of the Piccolo-encoding gene PCLO are reported to be associated with mental disorders. However, a few studies have evaluated the relationship between Piccolo dysfunction and psychotic symptoms. Therefore, we investigated the neurophysiological and behavioral phenotypes in mice with Piccolo suppression in the medial prefrontal cortex (mPFC). Downregulation of Piccolo in the mPFC reduced regional synaptic proteins, accompanied with electrophysiological impairments. The Piccolo-suppressed mice showed an enhanced locomotor activity, impaired auditory prepulse inhibition, and cognitive dysfunction. These abnormal behaviors were partially ameliorated by the antipsychotic drug risperidone. Piccolo-suppressed mice received mild social defeat stress showed additional behavioral despair. Furthermore, the responses of these mice to extracellular glutamate and dopamine levels induced by the optical activation of mPFC projection in the dorsal striatum (dSTR) were inhibited. Similarly, the Piccolo-suppressed mice showed decreased depolarization-evoked glutamate and -aminobutyric acid elevations and increased depolarization-evoked dopamine elevation in the dSTR. These suggest that Piccolo regulates neurotransmission at the synaptic terminal of the projection site. Reduced neuronal connectivity in the mPFC-dSTR pathway via suppression of Piccolo in the mPFC may induce behavioral impairments observed in schizophrenia.

Identification of Rare Mutations of Two Presynaptic Cytomatrix Genes BSN and PCLO in Schizophrenia and Bipolar Disorder

“…Furthermore, the PCLO-suppressed mice showed increasing stress vulnerability when under mild social defeat stress. Their neurophysiological experiment in this animal model suggests that PCLO suppression in the medial frontal cortex may reduce neuronal connectivity between the medial frontal cortex and dorsal lateral striatum and cause schizophrenia-like behavioral impairments [40].…”

“…Antipsychotic risperidone can partially improve these impairments in their study. [40]. Furthermore, the PCLO-suppressed mice showed increasing stress vulnerability when under mild social defeat stress.…”

Ablation of the Presynaptic Protein Mover Impairs Learning Performance and Decreases Anxiety Behavior in Mice

“…Rather, Mover may inhibit these functions of Bassoon or act independently, without physically interacting with Bassoon. Interestingly, Nitta et al (2021) demonstrated that downregulation of Piccolo, a presynaptic scaffolding protein structurally related to Bassoon, in the medial prefrontal cortex reduced recognition memory in the NOR [ 27 ].…”

Multi-Omics Analysis Reveals Myelin, Presynaptic and Nicotinate Alterations in the Hippocampus of G72/G30 Transgenic Mice

“…Recently, mutations in both Pclo and Bsn genes have been identified in subjects with schizophrenia [35], whereas increased Pclo gene expression was reported in the amygdala of schizophrenia patients [36]. Furthermore, mice with suppressed Pclo expression in the medial prefrontal cortex exhibited schizophrenia-like behaviors [37]. Intriguingly, in an interactome study of D-amino acid oxidase (DAO) in the rat cerebellum, both Bsn and Pclo were identified as DAO interacting proteins, and Bsn was shown to co-localize with DAO and inhibit its enzymatic activity [38], suggesting that Bsn may have a regulatory role in downstream, G72 (DAOA)-related pathways.…”