To test this, we used strains with impaired synaptic transmission caused by mutations in synaptic genes such as unc‐2/CACNA1A, unc‐18/Munc18, snt‐1/synaptotagmin, snb‐1/synaptobrevin, unc‐26/synaptojanin, unc‐10/Rim1, and unc‐11/AP180 (Fig. 3A) (Barclay et al., 2012; Bargmann, 2012).
Animals carrying mutations in synaptic components often exhibit uncoordinated movements (unc), egg-laying defects (egl), defecation defects or paralysis.
The identification and characterization of this mutation expands our understanding of the molecular mechanisms of epileptogenesis and further highlights that mutations in synaptic proteins cause epilepsy.
To test this prediction, we studied how resistance to oxidative stress and lifespan changed in response to antidepressant treatment and how these changes are affected by mutations in oxidative stress response genes and genes controlling synaptic transmission.
Recently, four independent research groups have reported that ANCL is caused by mutations in the DNAJC5 gene that encodes the endogenous neuroprotective synaptic chaperone cysteine string protein (CSP) [67 70].
The specific effect on synaptic function that this cluster of mutations interfere with remains to be identified, however, GRM1 plays an important role in synaptic scaling [48], a process that may be abrogated in schizophrenia [49] and perturbed by mutations in GRM1 that affect splicing.
Because RS has an autistic feature that is caused by epigenetic failure, it was speculated that autism can be caused not only by mutations of synaptic molecules (as described in the introduction) but also by the aberrant expression of these molecules; this has been confirmed, as a synaptic function has been proven for protocadherins, which depends on their targeting by MeCP2 [ 32].
The synaptic hypothesis was also confirmed by the discovery of mutations in trans-synaptic adhesion proteins, such as neuroligins and neurexins, in a small fraction of individuals with ASDs, which was proposed to alter synaptic homeostasis and/or impair synapse development[ 8, 9].
The understanding of how mutations in a "synaptic" protein can lead to lysosome dysfunction is currently unclear.
In contrast, diacylglycerol kinase‐1 (DGK‐1) represses synaptic exocytosis, and therefore, mutations in dgk‐1 enhance synaptic transmission (Nurrish et al., 1999).
Among AD animal models, TgCRND8 mice showed a more extensive spectrum of synaptic alterations compared to other AD mouse models, characterized by mutations only in the APP gene (APP23 and Tg2576 mice).
