Neuroligin - Synapse Formation

Synapse Formation

Neuroligin is sufficient to form new functional presynaptic terminals in vitro. However, evidence suggests that additional adhesion molecules, such as immunoglobulin-domain and cadherin family proteins, mediate the intial contact between the axons and dendrites for a synapse. Neurexins and neuroligins then reinforce the contact.

In addition to the selectivity of splice variants, the levels of neuroligins, neurexins, and other interacting proteins present on the pre- and postsynaptic membranes influence the differentiation and balance of synapses. As synapses form during synaptogenesis, they differentiate into one of two categories: excitatory or inhibitory. Excitatory synapses have increased probability of firing an action potential in the postsynaptic neuron and are often glutamatergic, or synapses in which the neurotransmitter glutamate is released. Inhibitory synapses have decreased probability of firing an action potential in the postsynaptic neuron and are often GABAergic, in which the neurotransmitter GABA is released. Especially during early development, neurons must receive an appropriate balance of excitatory vs. inhibitory synaptic input, referred to as the E/I ratio. In fact, an imbalance in the E/I ratio is thought to be involved in autistic spectrum disorders.

Neuroligin 1 localizes at excitatory synapses, neuroligin 2 at inhibitory synapses, and neuroligin 3 at both. Reduction in the levels of neuroligins 1, 2, and 3 results in a strong reduction of inhibitory input but little reduction in excitatory input. In addition, Neuroligin 1 interacts with PSD-95, an intracellular protein that anchors synaptic proteins in the post-synaptic density of neurons. Neuroligin 2 interacts with PSD-95 and gephyrin, an inhibitory postsynaptic scaffold molecule. The level of PSD-95 appears to influence the balance of excitatory and inhibitory inputs. An increase in the ratio of PSD-95 to neuroligin resulted in an increase in the E/I ratio, and a decrease in the PSD-95/neuroligin ratio had the opposite effect. Also, overexpression of PSD-95 redirects neuroligin-2 from excitatory to inhibitory synapses, strengthening excitatory input and reducing inhibitory input. These interactions of neuroligin, neurexin, and interacting proteins such as PSD-95 point to a potential regulatory mechanism that controls development and balance of excitatory and inhibitory synapses, governed by homeostatic feedback mechanisms.