The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

Abstract

The serine protease inhibitor neuroserpin regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin expression is particularly prominent at late stages of neuronal development in most regions of the central nervous system (CNS), whereas it is restricted to regions related to learning and memory in the adult brain. The physiological expression pattern of neuroserpin, its high degree of colocalization with tPA within the CNS, together with its dysregulation in neuropsychiatric disorders, suggest a role in formation and refinement of synapses. In fact, studies in cell culture and mice point to a role for neuroserpin in dendritic branching, spine morphology, and modulation of behavior. In this study, we investigated the physiological role of neuroserpin in the regulation of synaptic density, synaptic plasticity, and behavior in neuroserpin-deficient mice. In the absence of neuroserpin, mice show a significant decrease in spine-synapse density in the CA1 region of the hippocampus, while expression of the key postsynaptic scaffold protein PSD-95 is increased in this region. Neuroserpin-deficient mice show decreased synaptic potentiation, as indicated by reduced long-term potentiation (LTP), whereas presynaptic paired-pulse facilitation (PPF) is unaffected. Consistent with altered synaptic plasticity, neuroserpin-deficient mice exhibit cognitive and sociability deficits in behavioral assays. However, although synaptic dysfunction is implicated in neuropsychiatric disorders, we do not detect alterations in expression of neuroserpin in fusiform gyrus of autism patients or in dorsolateral prefrontal cortex of schizophrenia patients. Our results identify neuroserpin as a modulator of synaptic plasticity, and point to a role for neuroserpin in learning and memory.

Cntn4, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior

“…Reduced spine synapse density in the CA1 region of the hippocampus are observed in neuroserpin-deficient mice 56 . Neuroserpin regulates the adhesion protein N-cadherin, which similarly to the Contactin family has been linked to synapse formation 57 – 59 .…”

Lemon essential oil ameliorates age-associated cognitive dysfunction via modulating hippocampal synaptic density and inhibiting acetylcholinesterase

“…The synapse number is significantly decreased in APP/PS1 mice and is repaired by LEO treatment IHC staining for the presynaptic markers (IHC) staining for the presynaptic markers, synapsin-1 and synaptophysin, and postsynaptic marker, PSD95 was performed in both the hippocampal region and cerebral cortex ( Figure 5A to Figure 5E) to visualize presynaptic and postsynaptic expression. Additionally, synapsin-1, which is associated with the regulation of neurotransmitter release from presynaptic neuron terminals [47,48], is measured in the experiment ( Figure 5F). APP/PS1 mice with no LEO treatment showed decreased synaptophysin immunoreactivity in the hippocampus compared with that in WT mice (P < 0.01) ( Figure 5A and Figure 5J).…”

SAP97 regulates behavior and expression of schizophrenia risk enriched gene sets in mouse hippocampus

“…Our attention is drawn to three genes that were differentially expressed in the hippocampus of SAP97-cKO mice versus controls—serine peptidase inhibitors (serpins), as this group of genes has previously been reported in the literature to be associated with SCZ [ 41 – 46 ]. SERPING1 was found to be upregulated in postmortem brain tissue from SCZ patients [ 44 , 45 ].…”

“…Another well-studied member of the serpin family previously implicated in SCZ, but not directly by our RNAseq data, is neuroserpin ( SERPINI1 ). SERPINI1 is restricted to regions in the brain where synaptic changes are associated with learning and memory (cortex, hippocampus, amygdala, and olfactory bulb) [ 46 ]. SERPINI1 has also been implicated in dendrite growth, as overexpression studies in primary neurons leads to increased dendritic arborization and altered dendritic spine shape [ 47 ].…”