1. Introduction 
    The embryonic migration of GABAergic interneurons to the cortex is an essential step in the development of a mature brain. This process involves multiple attractive and repulsive chemical signalling cues to drive neurons from their point of origin in the subpallium and attract them to their terminal destination in the developing cortex. This review will begin with a brief overview of the anatomic regions that give rise to GABAergic interneurons, followed by a description of the molecular mechanisms that induce neurons to migrate from each of the regions subpallium and preoptic area to the telencephalon.  
2. Embryonic anatomy
     Two major regions within the subpallium produce interneurons: the ganglionic eminence (GE) and the preoptic area (POA) \cite{Gelman_2009}. The GE is further subdivided into the lateral (LGE), medial (MGE) (~55% of cortical interneurons \cite{Pleasure_2000}), and caudal (CGE) subregions (~30-40% of interneurons  \cite{Wonders_2008,Xu_2004}). 
    There are two main types of interneurons that are produced in the MGE based on transmembrane proteins that they uniquely express: Parvalbumin (PV), which promotes prolonged rapid depolarization, or somatostatin (SST), which favours burst firing or slower depolarizations  \cite{Wonders_2008,Xu_2004}.  The expression of the Nkx2.1 gene, which is modulated by the level ofSonic Hedgehog (Shh) signalling,  is unique to the MGE and dictates whether an interneuron will express SST or PV \cite{Xu_2004}.  The CGE meanwhile can express either Calretinin or Neuropeptide Y \cite{Lee_2010,Miyoshi_2010}. Interneurons from the CGE express an ionotropic serotonin receptor, 5hT3a, and generally end their migration in the superficial layers of the neocortex, regardless of when the cell was created \cite{Rudy_2010,Miyoshi_2010}. The POA, the least prolific progenitor region, produces Neuropeptide Y interneurons that terminate in the superficial layers of the cortex, as well as some PV and SST interneurons which end in the deeper cortical lamina \cite{Gelman_2009,Gelman_2011}. Therefore, the transmembrane proteins expressed by interneurons appear not only to influence the migratory trajectories of the interneurons, but also determine the computational role these interneurons will play in the neural circuitry of the fully developed neocortex. 
3. Chemorepellents
    Chemorepellents act by chemically discouraging interneurons from approaching regions that express them. Many chemorepellents are expressed in or near the GE, suggesting that they provide an initial impetus for the interneurons to begin their migration and also constrain the migratory pathways  \cite{Wichterle_2003,Zimmer2011}.
    Semaphorins are an important class of chemorepellents and have been linked to the guidance of interneurons. Marin et al. have reported that the effect of semaphorins (3A/3F) is modulated by whether or not the interneurons express neuropilin: those cells that do are guided to the cortex, whereas the rest terminate in the striatum\cite{Marin_2001}.  One study showed that Sema3a in conjunction with chondroitin sulphate keep interneurons from entering the striatal mantle zone \cite{Zimmer_2010}
    Ephrin is another chemorepellent that has has been found to help form migratory pathways based on the origin of the interneurons\cite{Zimmer2011}. Ephrin-A5 signalling from the ventricular zone repulses interneurons from the MGE, supporting the hypothesis that interneurons are driven to leave their points of origin by chemorepellents \cite{Zimmer_2008}. Interneurons migrating from the MGE express the EphA4 receptor, which is repelled by ephrin-A3 signalling from the developing striatum \cite{Rudolph_2010}. Similarly, interneurons originating from the POA express EphB1/3 and are repulsed by the ephrin-B3 expressed in the POA  \cite{Rudolph_2014}. This repulsion occurs because the activation of the EphB1 receptor induces the phosphorylation of Src and Fak, which creates a cascade the results in repulsion \cite{Rudolph_2014}.  A recent study has found that balance of both forward and reverse signalling, via Eph-B receptors and transmembrane ephrin proteins, seems to be essential for establishing the proper interneuron distribution  \cite{Talebian_2017}. Talebian et al. speculate that disruption to normal Ephrin-mediated forward/reverse signalling may underly neuropsychiatric diseases like schizophrenia, autism, and epilepsy, but evidence from humans is lacking  \cite{Talebian_2017}.  It may be possible address this by developing a PET radiotracer to target GABAergic interneurons, or even subclasses of these based on characteristic transmembrane proteins, to link (1) Ephrin-related genetic mutations, (2) abnormal patterns of interneuron distribution in adult humans and (3) neuropsychiatric illness.
    There is in vitro evidence that Slit and its receptor, Robo, form a chemorepulsive signalling mechanism for interneuron migration \cite{Zhu_1999}, but the actual role this plays for interneuron migration in vivo is not entirely clear.  Only rodents with mutations in Robo, but not Slit, show an abnormal distribution in the number of interneurons neurons \cite{Marin_2003,Andrews_2008}.  Nonetheless, because Slit-deficient rodents exhibit defects in the type of interneurons distributed in the cortex, it appears that Slit may play an important role for guiding cells once they have arrived at the cortex \cite{Marin_2003}. In accordance with Marin et al. \cite{Marin_2003}, Wichterle et al. found that the MGE is surrounded by inhibitory signalling containing Slit1 and Slit2, but that that Slit was not by itself enough to generate the repulsive signalling surrounding the MGE  \cite{Wichterle_2003}.
4. Chemoattractants 
    In addition to being pushed by chemorepellents, several signalling pathways have been implicated in attracting interneurons to the cortex. Neuregulin 1 (Nrg1) is a cell adhesion molecule that is expressed in a membrane-bound form in the LGE and an unbound isoform of Nrg1 in the cortex. It has an epidermal growth-factor domain that binds to the ErB4 in interneurons, the loss of which leads to an abnormal cortical interneuron distribution \cite{Flames_2005}. As previously mentioned, ephrin can also act as a chemoattractant via reverse signalling mediated by ephrin-A and B ligands \cite{Steinecke_2013}.
    Chemoattractants not only bring interneurons to the cortex but also help to determine where in the cortex the interneurons will go. CXCL12, via an interaction with CXCR4, acts is a chemoattractant for interneurons whose role is not so much to guide interneurons to the cortex, but rather to make sure they end up in the appropriate location and cortical layer \cite{Daniel_2005,Tiveron_2006,Stumm2003}.  Interneurons will normally avoid entering the cortical plate for approximately 48 hours after reaching the cortex, during which time they spread out tangentially  \cite{López-Bendito2008}. However, disturbing the usual CXCL12 and CXCR4 signalling leads to the early entry of the interneurons into the cortex and thus abnormal interneuron distribution \cite{López-Bendito2008}. CXCL12-CXCR4 are also important for getting interneurons to enter the migratory streams they will follow to the cortex \cite{Li2008}.
5. Neurotransmitters
    Neurotransmitters also appear to play a role in migration, especially GABA and dopamine. Migrating interneurons express increased sensitivity to GABA through an upregulation of GABAA and GABAB receptors \cite{Cuzon_2005,Cuzon_Carlson_2010}. Reducing GABA levels in the cortex leads to a decrease in the number of interneurons that cross into the cortical wall  \cite{Cuzon_2005,Lopez_Bendito_2003}. One study has found that an upregulation of the KCC2 potassium-chloride pump leads to a hyperpolarization of the neurons when GABAR channels are opened and thus serves to stop migration via GABA signalling  \cite{Bortone_2009}. In addition, migrating interneurons also have D1 and D2 dopamine receptors\cite{Crandall_2007,Ohtani2003}. Whereas interneurons without D1 receptors appear less able to migrate, D2 knockouts show an increased propensity for migration\cite{Crandall2007}. Neurotransmitters may play a role in halting interneuron migration. 
6. Discussion 
    An important and outstanding question that has recently caused controversy is whether interneurons from the same lineage go to the same cortical regions. While some researchers have reported that clonally related interneurons are randomly dispersed through the neocortex \cite{Harwell_2015,Mayer_2015}, others have reported that these interneurons tend to cluster together \cite{Brown_2011,Ciceri_2013}.  After having reanalyzed of the existing data and performed new experiments, Sultan et al. \cite{Sultan2016} concluded that clonally related interneurons do tend to form clusters, while Garcia et al. \cite{Turrero_Garc_a_2016} and Mayer et al. \cite{Mayer_2016} disagreed with this conclusion. This difference of opinion stems in part because Sultan et al.  \cite{Sultan2016} compare the clustering of clonally related interneurons to a null-distribution of cell clustering derived from computer simulation, whereas Mayer et al.  \cite{Mayer_2016} compared the clustering of clonally related interneurons to non-clonally related interneurons. 
    An important limitation of the studies reviewed in this paper is that their experimental methods only allow them to study one molecular signalling pathway at a time. This is clearly necessary in order to identify the individual molecular pathways involved in tangential migration but seems inadequate for understanding how these complex mechanisms work together dynamically. One method to address this, which is touched on in Sultan et al.  \cite{Sultan2016}, is to use computational simulation to model the many factors that determine tangential migration and arrive at a macroscopic understanding of the dynamics of these signalling pathways. While it remains to be seen whether computational modelling can be fruitfully applied to the brain as a whole--as in the much criticized Human Brain Project\cite{Markram_2012,Abbott_2015,Fr_gnac_2014}--it may prove useful in the much narrower context of neural migration during brain development. 
7. Conclusion
    The tangential migration of interneurons from the subpallium to the developping cortex is a complex process mediated both by chemoattraction and chemorepulsion. Many outstanding questions remain as to how these cues help form the complex circuitry of the neocortex and what role these play in neuropsychiatric disorders.