New research uncovers how Parkinson’s affects the brain

Parkinson’s is associated with a higher risk of cognitive impairment and dementia that can severely impact quality of life. Cognitive symptoms include deficits in attention and mental flexibility, among others, and can pre-date the tremors and rigidity used to diagnose the disease.

These and other cognitive abilities depend on the capacity of synapses to strengthen and weaken by dynamic addition or removal of neurotransmitter receptors within the synaptic membrane of relevant striatal and other neural circuits.

A new study published in the Proceedings of the National Academy of Sciences shows functional vulnerability in a circuit that does not degenerate in Parkinson’s and at a young age.

The researchers found that in mice genetically modified to carry a Parkinson’s-causing gene mutation, a subtype of receptor for the neurotransmitter glutamate accumulates abnormally on the cell surface of a class of neurons in the striatum important for attention and other cognitive functions.

Normally, a pool of waiting receptors can be rapidly recruited to synapses to dynamically increase synaptic strength, but in the Parkinson’s neurons, these receptors fail to be recruited to synapses under experimental conditions that normally strengthen synaptic responses.

Receptors are immobilized or trapped on the cell surface of Parkinson’s neurons compared to control neurons, unable to internalize, externalize, or even transit within the membrane, thus disrupting the molecular basis of synaptic plasticity essential for cognitive and other striatal functions.

Using mice genetically engineered to carry a Parkinson’s-causing gene mutation, the investigators applied high-resolution microscopy, biochemistry and electrophysiology to show that synapses on one type of striatal neurons important for executive function fail to strengthen because a subtype of glutamate receptor accumulates abnormally on the cell surface and become selectively trapped, unable to move in or out of synapses.

They showed that within an identified excitatory neural circuit in striatum, an AMPA-type glutamate receptor is excessively enriched on the surface both within and outside of synapses on the direct-pathway subtype of striatal projection neurons. The receptors are abnormally stable or trapped as they fail to internalize off the surface or to move readily within the plane of the membrane.

Receptors also fail to insert into the membrane when stimulated by paradigms that normally strengthen synapses. Thus, glutamate receptors are saturated and immobile at synapses on these striatal neurons, greatly limiting their function.

These actions restrict synaptic strength to a narrow operating range incompatible with dynamic receptor trafficking required for cognitive functions, and consistent with previous studies showing that these Parkinson’s mice display cognitive deficits. Significantly, the findings were consistent in developing and mature mice, which if replicated in humans, could be an early sign of cognitive risk, amenable to treatment prior to neural degeneration.

The research suggests that impaired dynamic and coordinated membrane trafficking of a subtype of glutamate receptors into and out of striatal synapses on direct-pathway striatal projection neurons underlies impairment in cognitive or other functions in Parkinson’s.