Cortical GABAergic Interneurons in Cross-Modal Plasticity following Early Blindness

Early loss of a given sensory input in mammals causes anatomical and functional modifications in the brain via a process called cross-modal plasticity. In the past four decades, several animal models have illuminated our understanding of the biological substrates involved in cross-modal plasticity. Progressively, studies are now starting to emphasise on cell-specific mechanisms that may be responsible for this intermodal sensory plasticity. Inhibitory interneurons expressing γ-aminobutyric acid (GABA) play an important role in maintaining the appropriate dynamic range of cortical excitation, in critical periods of developmental plasticity, in receptive field refinement, and in treatment of sensory information reaching the cerebral cortex. The diverse interneuron population is very sensitive to sensory experience during development. GABAergic neurons are therefore well suited to act as a gate for mediating cross-modal plasticity. This paper attempts to highlight the links between early sensory deprivation, cortical GABAergic interneuron alterations, and cross-modal plasticity, discuss its implications, and further provide insights for future research in the field

Plasticité intermodale chez le hamster énucléé à la naissance : Études de la distribution des interneurones CaBPir dans les cortex visuel et auditif primaires

La période postnatale et l’expérience sensorielle sont critiques pour le développement du système visuel. Les interneurones inhibiteurs exprimant l’acide γ-aminobutyrique (GABA) jouent un rôle important dans le contrôle de l’activité neuronale, le raffinement et le traitement de l’information sensorielle qui parvient au cortex cérébral. Durant le développement, lorsque le cortex cérébral est très susceptible aux influences extrinsèques, le GABA agit dans la formation des périodes critiques de sensibilité ainsi que dans la plasticité dépendante de l’expérience. Ainsi, ce système inhibiteur servirait à ajuster le fonctionnement des aires sensorielles primaires selon les conditions spécifiques d’activité en provenance du milieu, des afférences corticales (thalamiques et autres) et de l’expérience sensorielle. Certaines études montrent que des différences dans la densité et la distribution de ces neurones inhibiteurs corticaux reflètent les caractéristiques fonctionnelles distinctes entre les différentes aires corticales. La Parvalbumine (PV), la Calretinine (CR) et la Calbindine (CB) sont des protéines chélatrices du calcium (calcium binding proteins ou CaBPs) localisées dans différentes sous-populations d’interneurones GABAergiques corticaux. Ces protéines tamponnent le calcium intracellulaire de sorte qu’elles peuvent moduler différemment plusieurs fonctions neuronales, notamment l’aspect temporel des potentiels d’action, la transmission synaptique et la potentialisation à long terme. Plusieurs études récentes montrent que les interneurones immunoréactifs (ir) aux CaBPs sont également très sensibles à l’expérience et à l’activité sensorielle durant le développement et chez l’adulte. Ainsi, ces neurones pourraient avoir un rôle crucial à jouer dans le phénomène de compensation ou de plasticité intermodale entre les cortex sensoriels primaires. Chez le hamster (Mesocricetus auratus), l’énucléation à la naissance fait en sorte que le cortex visuel primaire peut être recruté par les autres modalités sensorielles, telles que le toucher et l’audition. Suite à cette privation oculaire, il y a établissement de projections ectopiques permanentes entre les collicules inférieurs (CI) et le corps genouillé latéral (CGL). Ceci a pour effet d’acheminer l’information auditive vers le cortex visuel primaire (V1) durant le développement postnatal. À l’aide de ce modèle, l’objectif général de ce projet de thèse est d’étudier l’influence et le rôle de l’activité sensorielle sur la distribution et l’organisation des interneurones corticaux immunoréactifs aux CaBPs dans les aires sensorielles visuelle et auditive primaires du hamster adulte. Les changements dans l’expression des CaBPs ont été déterminés d’une manière quantitative en évaluant les profils de distribution laminaire de ces neurones révélés par immunohistochimie. Dans une première expérience, nous avons étudié la distribution laminaire des CaBPs dans les aires visuelle (V1) et auditive (A1) primaires chez le hamster normal adulte. Les neurones immunoréactifs à la PV et la CB, mais non à la CR, sont distribués différemment dans ces deux cortex primaires dédiés à une modalité sensorielle différente. Dans une deuxième étude, une comparaison a été effectuée entre des animaux contrôles et des hamsters énucléés à la naissance. Cette étude montre que le cortex visuel primaire de ces animaux adopte une chimioarchitecture en PV similaire à celle du cortex auditif. Nos recherches montrent donc qu’une suppression de l’activité visuelle à la naissance peut influencer l’expression des CaBPs dans l’aire V1 du hamster adulte. Ceci suggère également que le type d’activité des afférences en provenance d’autres modalités sensorielles peut moduler, en partie, une circuiterie corticale en CaBPs qui lui est propre dans le cortex hôte ou recruté. Ainsi, nos travaux appuient l’hypothèse selon laquelle il serait possible que certaines de ces sous-populations d’interneurones GABAergiques jouent un rôle crucial dans le phénomène de la plasticité intermodale.The postnatal period and sensory experience are critical for the development of the visual system. The inhibitory interneurons expressing the γ-aminobutyric acid (GABA) play an important role in the control of neural activity, refinement and treatment of sensory information which reaches the cerebral cortex. During development, when the cerebral cortex is very likely to be influenced by extrinsic factors, GABA acts in the formation of critical period of receptivity as well as in experience dependent plasticity. Thus, this inhibitory system adjusts the functioning of the primary sensory areas according to the specific conditions of activity from the environment, cortical afferents (e.g. of thalamic origin), and sensory experience. Several studies show that differences in the distribution and density of these inhibitory interneurons tend to reflect functional discrepancies between the different neocortical areas. Parvalbumin (PV), Calretinin (CR) and Calbindin (CB) are calcium-binding proteins (CaBPs) found in different sub-populations of GABAergic cortical interneurons. These proteins buffer intracellular calcium levels, which can in turn modulate several neural functions, notably the temporal aspect of action potentials, synaptic transmission and long-term potentiation. Several recent studies are showing that CaBPs immunoreactive (ir) interneurons are also very sensitive to experience and sensory activity during development and adulthood. Therefore, these neurons may have a critical role in intermodal plasticity or compensatory processes between primary sensory cortices. In the hamster (Mesocricetus auratus), after enucleation at birth, the primary visual cortex can be recruited by other sensory modalities such as touch and audition. After this type of visual deprivation, there is establishment of permanent ectopic projections between the inferior colliculus (IC) and the lateral geniculate nucleus (LGN). This phenomenon leads to the rerouting of auditory information to the primary visual cortex (V1) during postnatal development. By using this animal model, the general objective of this thesis is to study the influence and the role of sensory activity on the distribution and organization of cortical interneurons that display immunoreactivity for CaBPs in the primary visual and auditory sensory areas in adult hamsters. Changes in the expression of CaBPs were quantitatively determined by assessing the laminar distribution profiles of cell bodies revealed by immunohistochemistry. In the first experiment, we studied laminar distribution of CaBPs in the primary visual (V1) and auditory (A1) cortices of normal hamsters. PVir and CBir, but not CRir neurons, are distributed in a dissimilar fashion between the two primary cortices devoted to each sensory modality. In the second study, a comparison was performed between control animals and hamsters which were enucleated at birth. The results of this study show that the primary visual cortex of these animals adopts a PVir chemoarchitecture similar to that of the auditory cortex. Our research shows that the abolition of visual activity at birth can influence the expression of CaBPs in V1 of the adult hamster. The present results also suggest that the type of activity in afferents from other sensory modalities can at least in part modulate the cortical circuitry of CaBPs in the host or recruited cortex. Thus, our work supports the hypothesis that sub-populations of GABAergic interneurons may play a critical role in the intermodal cortical plasticity

Effect of testosterone on lesioned females.

<p><b>A</b>) Photographs showing the effects of testosterone treatment on female anatomy at P10. Male rat (NM, left), female rat (NF, middle) and testosterone injected female (F+T, right) are shown. Testosterone exposure during the fetal and perinatal periods altered the development of secondary sex characteristics in female rat (F+T) pups such as the presence of a longer anogenital distance (top) and the lack of breast (bottom). <b>B</b>) EEG in an adult LHSF+T rat showing an example of an electrographic seizure. Seizure activity recorded over a 60-second period from the right primary motor cortex (M1, top trace) and hippocampus (CA1, bottom trace) ipsilateral to the lesion. <b>C</b>) Pre-seizure baseline rhythm was composed of irregular, low amplitude, 6 to 12 Hz frequency activity. In this case, the first behavioral manifestation was characterized by abrupt rearing and hind limb myoclonus associated with the slow wave polyspiking pattern shown by the first arrow. Interictal epileptic spike or spike and wave activity was also recorded frequently throughout this period (arrows 2 and 3). <b>D</b>) Just before the seizure, the epileptic discharges were intermingled with a burst of hippocampal fast activity (1), followed by a slow rhythmic activity at a frequency of 1 to 3 Hz (2) progressing into 6 to 8 Hz rhythmic activity (3). <b>E</b>) During the seizure the EEG trace showed a prolongation of the rhythmic activity characterized by high amplitude oscillations equivalent to two to ten-fold of baseline rhythm at a lower frequency range (5–7 Hz range). <b>F</b>) The end of the seizure (1) is marked by low amplitude fast activity intermingled with periodic epileptic discharges before a progressive return to theta activity (2). The clinical manifestations included freezing followed by myoclonus, and abrupt rearing and falling. Acquisition frequency was 200 Hz, and filtering at 1–35 Hz. Horizontal bar = 1 second; vertical bar = 500 µV.</p

Photomicrographs of cresyl violet sections and Cavalieri's cortical lesion volumes estimations in the adult rats.

<p>In <b>A</b>), a confirmation example of the bipolar electrodes placement for EEG recordings in a LHSF+T rat is shown in motor cortex M1 (left panel) and in the <i>cornus ammonis</i> region one (CA1) of the hippocampus (right panel). <b>B</b>) Cresyl violet stained coronal section through the dysplasic lesion in sensorimotor cortex of P120 rat brains, male (left) and female (right), that received a freeze-induced lesion at P1 and hyperthermic seizure at P10 (LHS). Photomicrographs are showing a similar and well-formed, four-layered microgyrus in the middle of each panel for both genders. In <b>C</b>), (Top panel) histograms of the volume estimations in the LHSM versus LHSF groups using the Cavalieri's principle for the focal mycrogyrus (left) and total amount of altered neocortex (right). (Bottom panel) diagrams illustrating the region of interest for sampling in each case highlighted with grid points. All Scale bars = 250 µm.</p

Latencies to behavioral generalized convulsion (GC) during hyperthermia at P10.

<p>Histograms showing that in the lesioned pups latency for GC is significantly shorter than in controls. This decrease is independent of gender and testosterone treatment (* = p<0.05, ** = p<0.01, *** = p<0.001).</p

Schematic table of study design, experimental groups and investigations.

<p><b>M</b>, Male; <b>F</b>, Female; <b>N</b>, naïve rats separated from the dam for a period equivalent to the surgery time in the L group at P1; <b>L</b>, animals simply subjected to cortical freeze lesion at P1; <b>HS</b>, only exposed to hyperthermia-induced febrile seizures at P10; <b>LHS</b>, submitted to the combination of cortical freeze lesion at P1 and hyperthermia seizures at P10; <b>L+T</b>, subjected to perinatal testosterone administration (from E16 to P9) and cortical freeze lesion at P1; <b>LHS+T</b>, perinatal testosterone treatment plus dual postnatal insults at P1 and P10.</p

Plasma corticosterone level (PCL) changes following treatments.

<p><b>A</b>) Histrograms showing changes in PCL before and after the cortical lesion in nmol/ml at P1 in males (top) and in females, bottom). <b>B</b>) Mean PCL variations for all the experimental groups in percentages. Note that the LM and LF+T groups were the only ones that showed an increase of corticosterone levels following cortical dysplasia induction at this age, whereas the others showed diminution. These increases were statistically different from their controls, notably LM compared to NM (*** p<0.001), LF+T compared to NF (* p<0.05) and to LF (** p<0.01).</p