PIN1, PSD-95, the Synapse, and Glyphosate
Postsynaptic density protein-95 (PSD-95) is a major regulator of
synaptic maturation. It interacts with NMDA receptors and
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors,
stabilizing and trafficking them to the postsynaptic membrane. PSD-95 is
involved in glutamatergic transmission, synaptic plasticity, and
dendritic spine morphogenesis during neurodevelopment. PSD-95 null mice
have learning and memory deficits and impaired socialization, associated
with increased NMDAR expression [142]. There is now overwhelming
evidence that PSD-95 disruption is associated with the cognitive and
learning deficits that are characteristic of autism and schizophrenia
[143,144].
Glyphosate exposure in rats has been shown to affect synaptic function.
Studies have demonstrated that glyphosate exposure leads to a decrease
in dendritic complexity, synaptic spine formation and maturation, and
synapse formation in hippocampal neurons. Glyphosate downregulates the
expression of synaptic proteins such as synapsin-1, PSD-95, and CaMKII,
and decreases PSD-95 clustering in the hippocampus. These changes in
synaptic assembly and protein expression likely contribute to the
impairment of cognitive function and neuronal connectivity in rats
exposed to glyphosate [145].
PSD-95 is a membrane-associated guanylate kinase, and it is the main
scaffolding protein at excitatory postsynaptic densities (PSDs). It
plays a major role in regulating synaptic strength and plasticity.
PSD-95 anchors NMDA receptors (NMDARs) in the PSD, thus increasing their
numbers. Phosphorylated PSD-95 recruits PIN1 to the synapse, and PIN1
controls the synaptic content of NMDARs via PSD-95 prolyl-isomerization.
PSD-95 has six potential PIN1 consensus motifs between the PDZ2 and PDZ3
domains, and binding of PIN1 following phosphorylation of the preceding
serine/threonine greatly influences its behavior [146].
Specifically, prolyl-isomerization following phosphorylation decreases
the ability of PSD-95 to complex with NMDARs, leading to a
downregulation of NMDAR-mediated synaptic transmission, and this is
associated with a decrease in dendritic spine density. Thus, PIN1
deficiency would be expected to result in upregulated NMDAR
expression and increased dendritic spine density. Indeed, PIN1
null mice have an increase in spine density [146], a feature that is
commonly associated with autism [147]. Upregulation of NMDARs at
neuronal synapses, along with increased glutamine synthetase expression
in astrocytes, has been linked to autism in a mouse model [148].
NMDAR expression was upregulated in the brain in another mouse model of
autism, and the NMDAR antagonist memantine was used to treat their
autistic-like behaviors [149]. Memantine has also been proposed to
have therapeutic value to treat autism in humans [150].
The term synaptopathy is used to describe brain disorders associated
with synaptic dysfunction. DLG4 is the gene that encodes PSD-95.DLG4 -related synaptopathy refers to a group of neurodevelopmental
disorders associated with variants in the DLG4 gene. Many of the
variants are de novo loss-of-function mutations, which may disrupt
binding to PIN1. These disorders are characterized by a broad range of
symptoms including global developmental delay, intellectual disability,
autism spectrum disorder, attention deficit-hyperactivity disorder, and
synaptic dysfunction [151].