Figure 5.

Potential mechanisms explaining the observed mismatched synapse formation of glutamatergic nerve terminals expressing α₂δ-2. A, Compensatory mechanism. Elevated expression of α₂δ subunits increases presynaptic calcium channel abundance and current densities and thus glutamate release. Therefore, GABA_ARs could be recruited to the dendritic spine in an attempt to compensate for excessive excitatory synaptic activity. If this is the case, then GABA_AR abundance at inhibitory synapses should not change upon α₂δ-2 overexpression in GABAergic presynaptic terminals. B, α₂δ-2 may be involved in trans-synaptically anchoring postsynaptic GABA_ARs. In this scenario, GABA_AR abundance should be increased when α₂δ-2 is overexpressed in both glutamatergic and GABAergic synapses. C, Trans-synaptic function of α₂δ-2 could also induce aberrant axonal wiring by guiding glutamatergic axons to GABAergic postsynaptic locations positioned along dendritic shafts. This is in contrast to the normal situation in which glutamatergic synapses are generally formed on dendritic spines.