New players tip the scales in the balance between excitatory and inhibitory synapses

Abstract

Synaptogenesis is a highly controlled process, involving a vast array of players which include cell adhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteins associated with the synaptic vesicle machinery. These molecules cooperate in an intricate manner on both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts. This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputs but virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight control of a balance between the types of synapses formed regulates the overall neuronal excitability, and is thus critical for normal brain function and plasticity. However, little is known about how this balance is achieved. This review discusses recent findings which provide clues to how neurons may control excitatory and inhibitory synapse formation, with focus on the involvement of the neuroligin family and PSD-95 in this process.

Figure 1

Neuroligins, β-neurexin, and PSD-95 modulate excitatory and inhibitory synapse formation. An example of the effects of a member of the neuroligin (NLG) family, NLG2 (green), on synapse formation. (A) Expression of NLG2 in hippocampal neurons increases the number of excitatory (VGLUT-positive; red) and inhibitory (VGAT-positive; blue) presynaptic contacts. (B) Interfering with β-neurexin and NLG2 coupling blocks NLG2 (green)-mediated effects on inhibitory synapse formation. Treatment with a soluble form of β-neurexin decreases the number of sites positive for VGAT (blue). (C) NLG2 (red) is normally localized at inhibitory synaptic contacts (VGAT-positive; blue; upper panel). Overexpression of PSD-95 shifts NLG2 from inhibitory to excitatory (PSD-95-positive; green) synapses (colocalization of NLG2 and PSD-95 appears in orange; lower panel).

Figure 2

Relative levels of scaffolding proteins and cell adhesion molecules control the balance between excitatory and inhibitory synapses. NLGs and PSD-95 are used here as an example to demonstrate this concept. Under normal conditions, NLG1 is enriched at excitatory contacts whereas NLG2 is concentrated at inhibitory synapses. PSD-95 retains the majority of NLG1 at excitatory synaptic sites, whereas NLG2 localization is primarily controlled through interaction with an unknown scaffolding protein specific to inhibitory synapses. An increase in the levels of PSD-95 results in a shift of NLG2 molecules from inhibitory to excitatory synapses, presumably through PDZ-mediated binding to PSD-95. The resulting effect is an overall increase in the number of excitatory relative to inhibitory synapses, and thus an enhanced excitatory to inhibitory (E/I) synaptic ratio (for simplicity, changes in synapse number are indicated by changes in the size of the illustrated presynaptic terminals). An altered E/I ratio may result in defects in brain circuitry associated with behavioral and cognitive abnormalities such as those linked to psychiatric, pain response, and learning and memory disorders.