Cortical interneurons in autism

Abstract

The mechanistic underpinnings of autism remain a subject of debate and controversy. Why do individuals with autism share an overlapping set of atypical behaviors and symptoms, despite having different genetic and environmental risk factors? A major challenge in developing new therapies for autism has been the inability to identify convergent neural phenotypes that could explain the common set of symptoms that result in the diagnosis. Although no striking macroscopic neuropathological changes have been identified in autism, there is growing evidence that inhibitory interneurons (INs) play an important role in its neural basis. In this Review, we evaluate and interpret this evidence, focusing on recent findings showing reduced density and activity of the parvalbumin class of INs. We discuss the need for additional studies that investigate how genes and the environment interact to change the developmental trajectory of INs, permanently altering their numbers, connectivity and circuit engagement.

Fig. 1 ∣. Evidence of parvalbumin-expressing cell hypofunction in autism.

There are several lines of converging evidence from human and animal studies that support a role of PV IN hypofunction in the pathogenesis of autism: (1) the density of PV INs is reduced; (2) the expression levels of PV protein are lower; (3) the density of PNNs around INs is decreased; (4) the power of baseline gamma oscillations (regulated by PV and SST INs) is increased; and (5) the activity of PV INs is decreased (for example, decreased visually evoked activity). FPKM, fragments per kilobase of transcript per million mapped reads.

Fig. 2 ∣. Genes and environment affect milestones of brain development in autism.

During human gestation, environmental insults and genetic risk factors can affect typical brain development at specific milestones, eventually leading to the symptoms of autism. These stressors could affect the birth and migration of neurons, their ability to form synaptic connections or generate the earliest forms of spontaneous network activity, and programmed cell death, as well as experience-dependent plasticity and learning. We propose that these changes occur at a critical stage when excitatory and inhibitory neurons participate in a structural and functional handshake (bracket and arrow). By the time symptoms of autism are recognized in toddlers, the circuit alterations may be irreversible, such that a complete restoration of typical network function (even with genetic rescue in single-gene autism disorders) may not be possible. However, it may be feasible to restore circuit function to a more typical regime by interventions after diagnosis. An approximate timeline of the equivalent stages of circuit formation in mice is also shown for comparison.

Fig. 3 ∣. Birth, migration and fate of cortical interneurons.

Cartoon of the typical trajectory of cortical IN development highlighting five critical stages of maturation that could proceed differently in autism. Many of the phenotypes observed in autism, whether reduced density of MGE-derived INs, mis-targeting of axons by PV neurons, network hypersynchrony or PV hypoactivity, could be traced back to an important checkpoint of postnatal development, when Pyr neurons and INs are first establishing functional connections (the 'handshake’). Whether one of these changes triggers the others and is the ultimate culprit of circuit dysfunction is not yet clear. a, Neurogenesis: birth of IN precursors at the MGE or caudal ganglionic eminence (CGE). Future PV and SST INs are generated in the CGE and express markers such as NKX2.1 and LHX6. b, Migration: MGE-derived and CGE-derived IN precursors migrate first tangentially and then radially into the cerebral cortex. Although cortical dysplasias described in some humans with autism could be explained by slower neuronal migration, changes in the migration of INs specifically have not been documented in autism. c, Apoptosis: a wave of developmental cell death in the second postnatal week is responsible for the loss of around 30% of cortical INs. Sensory-evoked and spontaneously generated cortical activity is responsible for this refinement in IN population density. Decreases in the intrinsic activity of INs (for example, due to immaturity) could lead to excessive death of INs in autism and explain the reduced density of PV neurons. d, Neurite extension: INs extend dendrites and axons in search of appropriate synaptic partners. IN hypoactivity could interfere with their ability to interact with Pyr neurons during an early acquaintance handshake or embrace between them. Immaturity of PV dendritic arbors has been reported in some mouse models of autism. e, Synaptic specialization: cortical INs eventually adopt their mature morphology and establish specialized synapses that target specific compartments of Pyr cells and other INs. This cell-type-specific structural connectivity is regulated by synaptic organizer proteins. It will be important to investigate whether differences exist in the expression of these genes, or in synaptic specificity, between autism models and controls.

Fig. 4 ∣. Shared phenotypes of parvalbumin cell hypofunction in rodent models of ASD.

This Venn diagram represents the shared phenotypes related to PV IN hypoactivity in rodent models of autism. Note that some of the models (for example, Lgdel and MIA) have also been linked to schizophrenia. VPA, valproic acid.