Science - USA (2021-11-05)

science.org SCIENCE

GRAPHIC: KELLIE HOLOSKI/

SCIENCE

INSIGHTS | PERSPECTIVES

B yDavid Blum^1 and Luísa V. Lopes^2

S

ynaptogenesis is a dynamic process

during normal brain development.

An overabundance of synapses is ini-

tially formed. Synaptic connectivity is

then refined through the elimination

of synapses. The essential process of

removing the irrelevant synapses during

this period is called synaptic pruning and is

a process regulated by neuronal activity ( 1 ),

commonly referred to as the “use it or lose

it” principle. This rapid period of synapto-

genesis early in life plays a vital role in net-

work wiring and affects learning, memory,

and brain adaptation later in life. On page

709 of this issue, Gomez-Castro et al. ( 2 )

provide a deeper look into this fundamen-

tal mechanism, showing that adenosine has

a key role in the activity-dependent stabi-

lization of inhibitory g-aminobutyric acid

(GABA) synapses.

The nucleoside adenosine is a build-

ing block of any cell, is crucial as a direct

and indirect component of RNA and DNA,

and is an important methyl donor for

epigenomic regulation; adenosine phos-

phorylation to form adenosine diphos-

phate (ADP) and adenosine triphosphate

(ATP) is directly involved in cellular me-

tabolism. Adenosine action on its four G

protein–coupled receptors (A 1 R, A2AR,

A2BR, and A 3 R) is also an essential process

in intercellular communication. In the

brain, extracellular adenosine increases as

a function of neuronal activity. It can be

formed either from the breakdown of ATP

coreleased with various neurotransmitters

upon neuronal stimulation or as a result of

intracellular catabolic activity. It then ac-

tivates pre- or postsynaptic adenosine re-

ceptors and modulates neuronal excitabil-

ity through, for example, feedback control

of neurotransmitter release and neuronal

activity or fine-tuning of long-term poten-

tiation ( 3 – 5 ). These processes allow for

the proper establishment of synaptic com-

munication and the control of excitability,

which affects specific functions such as

learning and memory.

Whether adenosine affects neuronal

development and synapse maturation has

been overlooked. Most knowledge was in-

ferred from studies using caffeine admin-

istration (an adenosine receptor blocker)

during pregnancy. Offspring of dams (preg-

nant mice) exposed to high doses of caf-

feine displayed an A2AR-dependent delayed

migration and insertion of GABA neurons

into circuits ( 6 ), leading to increased corti-

cal and hippocampal network excitability

and susceptibility to seizures in adulthood

( 6 , 7 ). This ultimately impairs cognition in

adulthood ( 6 , 8 ) but also accelerates mem-

ory impairment in a model of tauopathy

(a form of neurodegeneration) ( 9 ). More

recently, a role of A2AR in the radial migra-

tion of cortical projection neurons was de-

scribed in mice ( 10 ). This is an important

developmental process by which cortical

neurons travel from their birthplace to

their final position in the circuit. However,

the role of adenosine during synaptogen-

esis remained largely unknown.

Gomez-Castro et al. uncover a role

of adenosine in the crucial period for

GABAergic synaptic stabilization in the

mouse hippocampus. They describe a

transient peak in extracellular adenosine,

originating from activity-dependent ATP

breakdown, and A2AR expression at post-

natal days 4 to 9, coinciding with GABA

receptor peak at postnatal days 7 to 9 ( 11 ).

They show that the activation of A2AR by

activity-dependent adenosine formation

is crucial for maintaining GABAergic

synapses, whereas receptor ablation in

neurons results in synapse elimination.

This mechanism is not only important for

shaping circuits at these developmental

stages, it is crucial for memory formation

in adults. The authors elegantly demon-

strate the downstream involvement of

the calcium–calmodulin–adenylyl cyclase

pathway, protein kinase A activation, and

subsequent phosphorylation of gephyrin—

a central protein that ultimately anchors,

clusters, and stabilizes GABA receptors at

inhibitory synapses. This establishes aden-

osine as an important signal to detect ac-

tivation of GABAergic synapses and favor

their stabilization during development.

Impaired production of activity-formed

adenosine therefore favors elimination of

weak synapses.

Whether such developmental control is

more broadly engaged in the stabilization or

even pruning of other types of synapses re-

mains to be addressed. GABA is known to be

excitatory during early developmental stages

in a large variety of tissues and species, pro-

viding the initial excitatory drive in the ab-

sence of glutamatergic synapses ( 12 ). Perhaps

the mechanism described by Gomez-Castro

et al. has a broader effect on excitatory synap-

togenesis and may constitute a fundamental

aspect of early synapse stabilization.

Moreover, although the study of Gomez-

Castro et al. provides clear evidence of the

involvement of neuronal A2AR activation,

Allostatic brain

Neurodevelopment

Allostatic brain

Aging and neurodegeneration

Homeostatic brain

Enhanced adenosine tone and A2AR

expression allow g-aminobutyric acid

(GABA)–ergic synapse stabilization,

allowing proper network wiring.

Adenosine sets physiological

plasticity by acting

on pre- and postsynaptic

adenosine receptors.

Enhanced adenosine tone and

A2AR expression affect neuron-

glial dialog to promote synaptic

dysfunction or degeneration.

A2AR A^1 R

Microglial

synapse

pruning factors

Synapse

Microglial cell degeneration

Neuron

GABA

Adenosine

NEUROSCIENCE

Stabilizing synapses

Adenosine fine-tunes the fate of nascent

synapses in brain development

(^1) Lille Neuroscience & Cognition, Inserm UMR-S1172,
Alzheimer & Tauopathies, LabEx DISTALZ, Lille Cedex,
France.^2 Instituto de Medicina Molecular João Lobo
Antunes, Faculdade de Medicina, Universidade de Lisboa,
Lisboa, Portugal. Email: [email protected];
[email protected]
Allostatic regulation of synapse fate by adenosine
Adenosine A2A receptor (A2AR) signaling controls synaptic allostasis (adaptation to challenges) during development
and potentially in the aged brain, which modulates processes crucial for network and cognitive functions.
684 5 NOVEMBER 2021 • VOL 374 ISSUE 6568