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.
Highlights
Psychiatric disorders appear as abnormal behavioral and mental patterns that cause severe distress or disability to the individual
The Piccolo protein expression in the miPiccolo mice was suppressed in the medial prefrontal cortex (mPFC) (Student’s t-test, n = 6, p = 0.0122; Figure 1C)
We showed that local Piccolo suppression in the mPFC resulted in diminished paired-pulse facilitation and LTP in the same brain region
Summary
Psychiatric disorders appear as abnormal behavioral and mental patterns that cause severe distress or disability to the individual. Many patients with schizophrenia exhibit functional, structural, and metabolic abnormalities in the prefrontal cortex (PFC) in neuroimaging studies reporting on the effects of antipsychotic medications and cognitive remediation therapy [4]. It is thought that altered neuronal activity and connection in the PFC by the genetic and environmental insults is associated with the pathophysiology of schizophrenia [7,8,9]. A presynaptic protein encoded by the PCLO gene, plays a role in synaptic vesicle trafficking by interacting with several proteins in the presynaptic active zone [10,11,12,13,14]. Piccolo alteration in its function or expression could change the balance of circuit activity, the phenotypic effects to the brain circuits and behavior are necessary to be investigated. We investigated whether or not a causal relationship between Piccolo dysfunction and behavioral impairments in mental disorders could be established
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